C2-azaspiro iminothiazine dioxides as bace inhibitors, compositions, and their use

ABSTRACT

In its many embodiments, the present invention provides certain C2-azaspiro substituted iminothiazine dioxide compounds. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer&#39;s disease, are also disclosed.

FIELD OF THE INVENTION

This invention provides certain C2-azaspiro iminothiazine dioxidecompounds, and compositions comprising these compounds, as inhibitors ofBACE, which may be useful for treating or preventing pathologies relatedthereto.

BACKGROUND

Amyloid beta peptide (“Aβ”) is a primary component of β amyloid fibrilsand plaques, which are regarded as having a role in an increasing numberof pathologies. Examples of such pathologies include, but are notlimited to, Alzheimer's disease, Down's syndrome, Parkinson's disease,memory loss (including memory loss associated with Alzheimer's diseaseand Parkinson's disease), attention deficit symptoms (includingattention deficit symptoms associated with Alzheimer's disease (“AD”),Parkinson's disease, and Down's syndrome), dementia (includingpre-senile dementia, senile dementia, dementia associated withAlzheimer's disease, Parkinson's disease, and Down's syndrome),progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment (including olfactory impairmentassociated with Alzheimer's disease, Parkinson's disease, and Down'ssyndrome), β-amyloid angiopathy (including cerebral amyloid angiopathy),hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”),glaucoma, amyloidosis, type II diabetes, hemodialysis (β2 microglobulinsand complications arising therefrom), neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, Creutzfeld-Jakob disease,traumatic brain injury and the like.

Aβ peptides are short peptides which are made from the proteolyticbreak-down of the transmembrane protein called amyloid precursor protein(“APP”). Aβ peptides are made from the cleavage of APP by β-secretaseactivity at a position near the N-terminus of Aβ, and by gamma-secretaseactivity at a position near the C-terminus of Aβ. (APP is also cleavedby α-secretase activity, resulting in the secreted, non-amyloidogenicfragment known as soluble APPα) Beta site APP Cleaving Enzyme (“BACE-1”)is regarded as the primary aspartyl protease responsible for theproduction of Aβ by β-secretase activity. The inhibition of BACE-1 hasbeen shown to inhibit the production of Aβ.

AD is estimated to afflict more than 20 million people worldwide and isbelieved to be the most common cause of dementia. AD is a diseasecharacterized by degeneration and loss of neurons and also by theformation of senile plaques and neurofibrillary tangles. Presently,treatment of Alzheimer's disease is limited to the treatment of itssymptoms rather than the underlying causes. Symptom-improving agentsapproved for this purpose include, for example, N-methyl-D-aspartatereceptor antagonists such as memantine (Namenda®, ForestPharmaceuticals, Inc.), cholinesterase inhibitors such as donepezil(Aricept®, Pfizer), rivastigmine (Exelon®, Novartis), galantamine(Razadyne Reminyl®), and tacrine (Cognex®).

In AD, Aβ peptides, formed through β-secretase and gamma-secretaseactivity, can form tertiary structures that aggregate to form amyloidfibrils. Aβ peptides have also been shown to form Aβ oligomers(sometimes referred to as “Aβ aggregates” or “Abeta oligomers”). Aβoligomers are small multimeric structures composed of 2 to 12 Aβpeptides that are structurally distinct from Aβ fibrils. Amyloid fibrilscan deposit outside neurons in dense formations known as senile plaques,neuritic plaques, or diffuse plaques in regions of the brain importantto memory and cognition. Aβ oligomers are cytotoxic when injected in thebrains of rats or in cell culture. This Aβ plaque formation anddeposition and/or Aβ oligomer formation, and the resultant neuronaldeath and cognitive impairment, are among the hallmarks of ADpathophysiology. Other hallmarks of AD pathophysiology includeintracellular neurofibrillary tangles comprised of abnormallyphosphorylated tau protein, and neuroinflammation.

Evidence suggests that Aβ, Aβ fibrils, aggregates, oligomers, and/orplaque play a causal role in AD pathophysiology. (Ohno et al.,Neurobiology of Disease, No. 26 (2007), 134-145). Mutations in the genesfor APP and presenilins 1/2 (PS1/2) are known to cause familial AD andan increase in the production of the 42-amino acid form of Aβ isregarded as causative. Aβ has been shown to be neurotoxic in culture andin vivo. For example, when injected into the brains of aged primates,fibrillar Aβ causes neuronal cell death around the injection site. Otherdirect and circumstantial evidence of the role of Aβ in Alzheimeretiology has also been published.

BACE-1 has become an accepted therapeutic target for the treatment ofAlzheimer's disease. For example, McConlogue et al., J. Bio. Chem., Vol.282, No. 36 (September 2007), have shown that partial reductions ofBACE-1 enzyme activity and concomitant reductions of Aβ levels lead to adramatic inhibition of Aβ-driven AD-like pathology, making β-secretase atarget for therapeutic intervention in AD. Ohno et al. Neurobiology ofDisease, No. 26 (2007), 134-145, report that genetic deletion of BACE-1in 5XFAD mice abrogates Aβ generation, blocks amyloid deposition,prevents neuron loss found in the cerebral cortex and subiculum (brainregions manifesting the most severe amyloidosis in 5XFAD mice), andrescues memory deficits in 5XFAD mice. The group also reports that Aβ isultimately responsible for neuron death in AD and concludes that BACE-1inhibition has been validated as an approach for the treatment of AD.Roberds et al., Human Mol. Genetics, 2001, Vol. 10, No. 12, 1317-1324,established that inhibition or loss of β-secretase activity produces noprofound phenotypic defects while inducing a concomitant reduction inAβ. Luo et al., Nature Neuroscience, Vol. 4, No. 3, March 2001, reportthat mice deficient in BACE-1 have normal phenotype and abolishedβ-amyloid generation.

More recently, Jonsson, et al. have reported in Nature, Vol. 488, pp.96-99 (August 2012), that a coding mutation (A673T) in the APP geneprotects against Alzheimer's disease and cognitive decline in theelderly without Alzheimer's disease. More specifically, the A allele ofrs63750847, a single nucleotide polymorphism (SNP), results in analanine to threonine substitution at position 673 in APP (A673T). ThisSNP was found to be significantly more common in a healthy elderlycontrol group than in an Alzheimer's disease group. The A673Tsubstitution is adjacent to the aspartyl protease beta-site in APP, andresults in an approximately 40% reduction in the formation ofamyloidogenic peptides in a heterologous cell expression system invitro. Jonsson, et al. report that an APP-derived peptide substratecontaining the A673T mutation is processed 50% less efficiently bypurified human BACE1 enzyme when compared to a wild-type peptide.Jonsson et al. indicate that the strong protective effect of theAPP-A673T substitution against Alzheimer's disease provides proof ofprinciple for the hypothesis that reducing the beta-cleavage of APP mayprotect against the disease.

BACE-1 has also been identified or implicated as a therapeutic targetfor a number of other diverse pathologies in which Aβ or Aβ fragmentshave been identified to play a causative role. One such example is inthe treatment of AD-type symptoms of patients with Down's syndrome. Thegene encoding APP is found on chromosome 21, which is also thechromosome found as an extra copy in Down's syndrome. Down's syndromepatients tend to acquire AD at an early age, with almost all those over40 years of age showing Alzheimer's-type pathology. This is thought tobe due to the extra copy of the APP gene found in these patients, whichleads to overexpression of APP and therefore to increased levels of Aβcausing the prevalence of AD seen in this population. Furthermore,Down's patients who have a duplication of a small region of chromosome21 that does not include the APP gene do not develop AD pathology. Thus,it is thought that inhibitors of BACE-1 could be useful in reducingAlzheimer's type pathology in Down's syndrome patients.

Another example is in the treatment of glaucoma (Guo et al., PNAS, Vol.104, No. 33, Aug. 14, 2007). Glaucoma is a retinal disease of the eyeand a major cause of irreversible blindness worldwide. Guo et al. reportthat Aβ colocalizes with apoptotic retinal ganglion cells (RGCs) inexperimental glaucoma and induces significant RGC cell loss in vivo in adose- and time-dependent manner. The group report having demonstratedthat targeting different components of the Aβ formation and aggregationpathway, including inhibition of β-secretase alone and together withother approaches, can effectively reduce glaucomatous RGC apoptosis invivo. Thus, the reduction of Aβ production by the inhibition of BACE-1could be useful, alone or in combination with other approaches, for thetreatment of glaucoma.

Another example is in the treatment of olfactory impairment. Getchell etal., Neurobiology of Aging, 24 (2003), 663-673, have observed that theolfactory epithelium, a neuroepithelium that lines the posterior-dorsalregion of the nasal cavity, exhibits many of the same pathologicalchanges found in the brains of AD patients, including deposits of AP,the presence of hyperphosphorylated tau protein, and dystrophic neuritesamong others. Other evidence in this connection has been reported byBacon A W, et al., Ann NY Acad Sci 2002; 855:723-31; Crino P B, Martin JA, Hill W D, et al., Ann Otol Rhinol Laryngol, 1995; 104:655-61; DaviesD C, et al., Neurobiol Aging, 1993; 14:353-7; Devanand D P, et al., Am JPsychiatr, 2000; 157:1399-405; and Doty R L, et al., Brain Res Bull,1987; 18:597-600. It is reasonable to suggest that addressing suchchanges by reduction of Aβ by inhibition of BACE-1 could help to restoreolfactory sensitivity in patients with AD.

For compounds which are inhibitors of BACE-2, another example is in thetreatment of type-II diabetes, including diabetes associated withamyloidogenesis. BACE-2 is expressed in the pancreas. BACE-2immunoreactivity has been reported in secretory granules of beta cells,co-stored with insulin and IAPP, but lacking in the other endocrine andexocrine cell types. Stoffel et al., WO2010/063718, disclose the use ofBACE-2 inhibitors in the treatment of metabolic diseases such as Type-IIdiabetes. The presence of BACE-2 in secretory granules of beta cellssuggests that it may play a role in diabetes-associated amyloidogenesis.(Finzi, G. Franzi, et al., Ultrastruct Pathol. 2008 November-December;32(6):246-51.)

Other diverse pathologies characterized by the formation and depositionof Aβ or fragments thereof, and/or by the presence of amyloid fibrils,oligomers, and/or plaques, include neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, traumatic brain injury (“TBI”),Creutzfeld-Jakob disease and the like, type II diabetes (which ischaracterized by the localized accumulation of cytotoxic amyloid fibrilsin the insulin producing cells of the pancreas), and amyloid angiopathy.In this regard reference can be made to the patent literature. Forexample, Kong et al., US2008/0015180, disclose methods and compositionsfor treating amyloidosis with agents that inhibit Aβ peptide formation.As another example, Loane, et al. report the targeting of amyloidprecursor protein secretases as therapeutic targets for traumatic braininjury. (Loane et al., “Amyloid precursor protein secretases astherapeutic targets for traumatic brain injury”, Nature Medicine,Advance Online Publication, published online Mar. 15, 2009.) Still otherdiverse pathologies characterized by the inappropriate formation anddeposition of Aβ or fragments thereof, and/or by the presence of amyloidfibrils, and/or for which inhibitor(s) of BACE-1 is expected to be oftherapeutic value are discussed further hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides certain C2-azaspiro iminothiazine dioxidecompounds, which are collectively or individually referred to herein as“compound(s) of the invention”, as described herein. The compounds ofthe invention are useful as inhibitors of BACE-1 and/or BACE-2.

In one embodiment, the compounds of the invention have the structuralFormula (I):

or a tautomer thereof having the structural Formula (I′):

or pharmaceutically acceptable salt thereof, wherein:

R^(1A) is selected from the group consisting of H, halo, alkyl,cycloalkyl, haloalkyl, and heteroalkyl;

R^(1B) is selected from the group consisting of H, halo, alkyl,cycloalkyl, haloalkyl, and heteroalkyl;

ring C is a moiety selected from the group consisting of

each R² is independently selected from the group consisting of H,-alkyl-OH, alkyl, heteroalkyl, and cycloalkyl wherein each said alkyl,heteroalkyl, and cycloalkyl of R² is optionally substituted withhalogen;

each R³ is independently selected from the group consisting of H,halogen, -alkyl-OH, alkyl, heteroalkyl, alkoxy, and cycloalkyl, whereineach said alkyl, heteroalkyl, alkoxy, and cycloalkyl of R³ is optionallysubstituted with halogen;

R^(N) is selected from the group consisting of: H, —C(O)R^(6N),—C(O)OR^(6N), —C(O)N(R^(6N))₂, —S(O)₂R^(6N), —S(O)₂N(R^(6N))₂, alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl,

wherein said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,

heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,heteroaryl,

and -alkyl-heteroaryl, of R^(N) are each optionally independentlyunsubstituted or

substituted with one or more groups independently selected from R⁹;

each R^(6N) (when present) is independently selected from the groupconsisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl;

wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl of R^(6N) is unsubstituted or substituted with one ormore groups independently selected from halogen, alkyl, cycloalkyl,heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy;

R⁴ is selected from the group consisting of H, alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl is optionally substituted with one or morehalogen;

ring A is selected from the group consisting of aryl, monocyclicheteroaryl, and a multicyclic group;

m is 0 or more;

each R^(A) (when present) is independently selected from the groupconsisting of:

-   halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5A))₃, —N(R^(6A))₂,    —OR^(6A), —SR^(6A), alkyl, heteroalkyl,-   alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,    and -alkyl-heterocycloalkyl, wherein said alkyl, heteroalkyl,    alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,    and -alkyl-heterocycloalkyl of R^(A) are each optionally    independently unsubstituted or substituted with one or more groups    independently selected from R⁸; -L₁- is a divalent moiety selected    from the group consisting-   of —NHC(O)— and —C(O)NH—;

R^(L) is selected from the group consisting of alkyl and heteroalkyl,wherein said alkyl and heteroalkyl of R^(L) are each optionallyunsubstituted or substituted with one or more halogen;

or, alternatively, R^(L) is a moiety having the formula

wherein q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of lower alkyl and lower heteroalkyl, wherein each said loweralkyl and lower heteroalkyl is optionally substituted with one or morehalogen;

ring B is selected from the group consisting of aryl, monocyclicheteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclicheterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclicgroup;

p is 0 or more; and

each R^(B) (when present) is independently selected from the groupconsisting of: halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5B))₃,—N(R^(6B))₂, —NR^(7B)C(O)R^(6B), —NR^(7B)S(O)₂R^(6B),—NR^(7B)S(O)₂N(R^(6B))₂, —NR^(7B)C(O)N(R^(6B))₂, —NR^(7B)C(O)OR^(6B),—C(O)R^(6B), —C(O)OR^(6B), —C(O)N(R^(6B))₂, —S(O)R^(6B), —S(O)₂R^(6B),—S(O)₂N(R^(6B))₂, —OR^(6B), —SR^(6B), alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl.

-   -   wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,        -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl,        aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, of R^(B)        are each optionally independently unsubstituted or substituted        with one or more groups independently selected from R⁹;

-   each R^(5A) and R^(5B) (when present) is independently selected from    the group consisting of alkyl, heteroalkyl, cycloalkyl,    -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl,    wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,    heterocycloalkyl, -alkyl-heterocycloalkyl of R^(5A) and R^(5B) is    unsubstituted or substituted with one or more halogen;

each R^(6A) (when present) is independently selected from the groupconsisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl,

wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, aryl of R^(6A) is unsubstituted or substitutedwith one or more groups independently selected from halogen, alkyl,cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, andhaloalkoxy;

each R^(6B) (when present) is independently selected from the groupconsisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl,

-   -   wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl,        heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,        heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,        heteroaryl, and -alkyl-heteroaryl of R^(6B) is unsubstituted or        substituted with one or more groups independently selected from        halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy,        heteroalkoxy, and haloalkoxy;

each R^(7B) (when present) is independently selected from the groupconsisting of H, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, and -alkyl-heterocycloalkyl,

-   -   wherein each said alkyl, heteroalkyl, -heteroalkyl-OH,        cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and        -alkyl-heterocycloalkyl of R^(7B) is unsubstituted or        substituted with one or more halogen;

each R⁸ (when present) is independently selected from the groupconsisting of halogen, lower alkyl, lower heteroalkyl, lower alkoxy,lower cycloalkyl, and lower heterocycloalkyl, wherein each said loweralkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lowerheterocycloalkyl of R⁸ is optionally substituted with halogen; and

each R⁹ (when present) is independently selected from the groupconsisting of halogen, —OH, —CN, —SF₅, —OSF₅, alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl,

cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-het erocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-het erocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl are optionally substituted with one or morehalogen.

In other embodiments, the invention provides compositions, includingpharmaceutical compositions, comprising one or more compounds of theinvention (e.g., one compound of the invention), or a tautomer thereof,or a pharmaceutically acceptable salt or solvate of said compound(s)and/or said tautomer(s), optionally together with one or more additionaltherapeutic agents, optionally in an acceptable (e.g., pharmaceuticallyacceptable) carrier or diluent.

In other embodiments, the invention provides various methods oftreating, preventing, ameliorating, and/or delaying the onset of an Aβpathology and/or a symptom or symptoms thereof, comprising administeringa composition comprising an effective amount of one or more compounds ofthe invention, or a tautomer thereof, or pharmaceutically acceptablesalt or solvate of said compound(s) and/or said tautomer(s), to apatient in need thereof. Such methods optionally additionally compriseadministering an effective amount of one or more additional therapeuticagents suitable for treating the patient being treated.

These and other embodiments of the invention, which are described indetail below or will become readily apparent to those of ordinary skillin the art, are included within the scope of the invention.

DETAILED DESCRIPTION

For each of the following embodiments, any variable not explicitlydefined in the embodiment is as defined in Formula (I) or (IA). In eachof the embodiments described herein, each variable is selectedindependently of the other unless otherwise noted.

In one embodiment, the compounds of the invention have the structuralFormula (IA):

or a tautomer thereof having the structural Formula (IA′):

or pharmaceutically acceptable salt thereof, wherein each variable is asdescribed in Formula (I).

In one embodiment, in each of Formulas (I), (IA), and (IA′), each R⁹(when present) is independently selected from the group consisting ofhalogen, —NO₂, —OH, —CN, —SF₅, —OSF₅, alkyl, -alkyl-OH, heteroalkyl,-heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,—O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl,wherein each said alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH,alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl,—O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-het erocycloalkyl,—O-heterocycloalkyl and —O-alkyl-heterocycloalkyl are optionallysubstituted with one or more halogen.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(N) isselected from the group consisting of H, —C(O)CH₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)O-cyclopropyl,—C(O)O—CH₂-cyclopropyl, —C(O)N(CH₃)₂, —C(O)NHCH₃, —C(O)-aryl,C(O)-heteroaryl, —S(O)₂CH₃, —S(O)₂-cyclopropyl, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —S(O)₂-aryl, —S(O)₂-heteroaryl, methyl, ethyl, propyl,isopropyl, cyclopropyl, —CH₂-cyclopropyl, benzyl, phenyl, pyridyl,pyrimidinyl, pyrazinyl, oxadiazoyl, isoxazoyl, oxazoyl, pyrrolyl,thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, —CH₂-heteroaryl,wherein said benzyl, phenyl, pyridyl, oxadiazoyl, isoxazoyl, oxazoyl,pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl,—CH₂-heteroaryl, C(O)-aryl, C(O)-heteroaryl, —S(O)₂-aryl,—S(O)₂-heteroaryl of R^(N) are each optionally unsubstituted orsubstituted with R⁹.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1A) isselected from the group consisting of H, halo, lower alkyl, lowercycloalkyl, lower haloalkyl, and lower heteroalkyl.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1A) isselected from the group consisting of H, fluoro, methyl, ethyl,cyclopropyl, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1A) isH.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1B) isselected from the group consisting of H, halo, lower alkyl, lowerhaloalkyl, and lower heteroalkyl.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1B) isselected from the group consisting of H, fluoro, methyl, ethyl,cyclopropyl, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1B) isH.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1A) isselected from the group consisting of H, halo, lower alkyl, lowercycloalkyl, lower haloalkyl, and lower heteroalkyl; and R^(1B) is H.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1A) isselected from the group consisting of H, fluoro, methyl, ethyl,cyclopropyl, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃; and R^(1B) is H.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1A) isH; and R^(1B) is selected from the group consisting of H, halo, loweralkyl, lower cycloalkyl, lower haloalkyl, and lower heteroalkyl.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1A) isH; and R^(1B) is selected from the group consisting of H, fluoro,methyl, ethyl, cyclopropyl, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R^(1B) is Hand R^(1A) is H.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R⁴ isselected from the group consisting of —CH₃, —CH₂F, —CHF₂, and —CF₃.

In one embodiment, in each of Formulas (I), (IA), and (IA′), R⁴ isselected from the group consisting of —CH₃, and —CHF₂.

In one embodiment, in each of Formulas (I), (IA), and (IA′):

R⁴ is selected from the group consisting of —CH₃ and —CHF₂; and

one of R^(1A) and R^(1B) is H and the other is selected from the groupconsisting of H, halo, lower alkyl, lower cycloalkyl, lower haloalkyl,and lower heteroalkyl.

In one embodiment, in each of Formulas (I), (IA), and (IA′):

R⁴ is selected from the group consisting of —CH₃ and —CHF₂; and

one of R^(1A) and R^(1B) is H and the other is selected from the groupconsisting of H, fluoro, methyl, ethyl, cyclopropyl, —CH₂F, —CHF₂, —CF₃,—CH₂OCH₃.

In one embodiment, in each of Formulas (I), (IA), and (IA′):

R⁴ is selected from the group consisting of —CH₃ and —CHF₂;

R^(1A) is H; and

R^(1B) is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is independently selected from the group consisting of H,methyl, ethyl, propyl, —CH₂OH, —CH₂ CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃,cyclopropyl, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is independently selected from the group consisting of H,methyl, ethyl, —CH₂OH, —CH₂OCH₃, cyclopropyl, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is independently selected from the group consisting of H,methyl, —CH₂OH, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ (when present) is independently selected from the groupconsisting of H, fluoro, chloro, methyl, ethyl,

propyl, —CH₂OH, —CH₂CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —OCH₃, —OCH₂CH₃,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F,—OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ (when present) is independently selected from the groupconsisting of H, fluoro, methyl, ethyl, —CH₂OH, —CH₂OCH₃, —OCH₃,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCHF₂, and —OCH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ (when present) is independently selected from the groupconsisting of H, methyl, —CH₂OH, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ (when present) is H.

Alternative embodiments for R^(N) in each of Formulas (I), (I′), (IA),and (IA′) are as follows:

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) group is selected from the group consisting of H, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)O-cyclopropyl,—C(O)O—CH₂-cyclopropyl, —C(O)N(CH₃)₂, —C(O)NHCH₃, C(O)-aryl,C(O)-heteroaryl, —S(O)₂CH₃, —S(O)₂-cyclopropyl, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —S(O)₂-aryl, —S(O)₂-heteroaryl, methyl, ethyl, propyl,isopropyl, cyclopropyl, —CH₂-cyclopropyl, benzyl, phenyl, pyridyl,pyrimidinyl, pyrazinyl, oxadiazoyl, isoxazoyl, oxazoyl, pyrrolyl,thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, —CH₂-heteroaryl,

wherein said benzyl, phenyl, pyridyl, oxadiazoyl, isoxazoyl, oxazoyl,pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl,—CH₂-heteroaryl, C(O)-aryl, C(O)-heteroaryl, —S(O)₂-aryl,—S(O)₂-heteroaryl of R^(N) are each optionally unsubstituted orsubstituted with R⁹.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) group is selected from the group consisting of H, —C(O)CH₃,—S(O)₂CH₃, —C(O)NHCH₃, methyl, ethyl, propyl, isopropyl, cyclopropyl,—CH₂-cyclopropyl, benzyl, and phenyl, wherein said benzyl and saidphenyl of R^(N) are each optionally unsubstituted or substituted withR⁹. In one such embodiment, R⁹ is selected from the group consisting ofhalogen, —NO₂, —OH, —CN, —SF₅, —OSF₅, alkyl, -alkyl-OH, heteroalkyl,-heteroalkyl-OH, and alkoxy. In another such embodiment, R⁹ is —NO₂. Inanother such embodiment, R^(N) is phenyl and R⁹ is —NO₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) group is selected from the group consisting of H, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)O-cyclopropyl,—C(O)O—CH₂-cyclopropyl, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂-cyclopropyl, —S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, methyl, ethyl, propyl,isopropyl, cyclopropyl, —CH₂-cyclopropyl, phenyl, and benzyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) group is selected from the group consisting of H, methyl, ethyl,propyl, isopropyl, cyclopropyl, and —CH₂-cyclopropyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) group is selected from the group consisting of H, —C(O)CH₃,—S(O)₂CH₃, —C(O)NHCH₃, methyl, benzyl, benzyl substituted with —NO₂,phenyl, and phenyl substituted with —NO₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) group is selected from the group consisting of methyl, ethyl,propyl, and isopropyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) group is methyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is H; and

each R³ (when present) is independently selected from the groupconsisting of H and fluorine.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′), R⁴ isselected from the group consisting of H, methyl, ethyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂F, —CHF₂, —CF₃, and —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′), R⁴ isselected from the group consisting of methyl, cyclopropyl, —CH₂F, and—CHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′), R⁴ isselected from the group consisting of methyl and —CHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

-   -   each R² is H;

each R³ (when present) is independently selected from the groupconsisting of H and fluorine; and

R⁴ is selected from the group consisting of methyl and —CHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is:

and

each R² and R^(N) is as defined in Formula (I).

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is:

and

each R², each R³, and R^(N) is as defined in Formula (I).

In an alternative of the immediately preceding embodiment, each R² is H;

Each R³ is independently selected from the group consisting of H andfluorine;

R⁴ is selected from the group consisting of methyl and —CHF₂; and

R^(N) is selected from any of the alternative embodiments for R^(N)described above.

In another alternative of the two immediately preceding embodiments,R^(N) is selected from the group consisting of H, —C(O)CH₃, —S(O)₂CH₃,—C(O)NHCH₃, methyl, ethyl, propyl, isopropyl, cyclopropyl,—CH₂-cyclopropyl, benzyl, and phenyl,

wherein said benzyl and said phenyl of R^(N) are each optionallyunsubstituted or substituted with R⁹. In one such embodiment, R⁹ isselected from the group consisting of halogen, —NO₂, —OH, —CN, —SF₅,—OSF₅, alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, and alkoxy. Inanother such embodiment, R⁹ is —NO₂. In another such embodiment, R^(N)is phenyl and R⁹ is —NO₂.

In yet another alternative of said two immediately precedingembodiments, R^(N) is selected from the group consisting of H, —C(O)CH₃,—S(O)₂CH₃, —C(O)NHCH₃, methyl, benzyl, benzyl substituted with —NO₂,phenyl, and phenyl substituted with —NO₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is: selected from the group consisting of

and

each R², each R³, and R^(N) is as defined in Formula (I).

In an alternative of the immediately preceding embodiment, each R² is H;each R³ is independently selected from the group consisting of H andfluorine;

R⁴ is selected from the group consisting of methyl and —CHF₂; and

R^(N) is selected from any of the alternative embodiments for R^(N)described above.

In another alternative of the immediately preceding embodiment, R^(N) isselected from the group consisting of H, —C(O)CH₃, —S(O)₂CH₃,—C(O)NHCH₃, methyl, ethyl, propyl, isopropyl, cyclopropyl,—CH₂-cyclopropyl, benzyl, and phenyl,

wherein said benzyl and said phenyl of R^(N) are each optionallyunsubstituted or substituted with R⁹. In one such embodiment, R⁹ isselected from the group consisting of halogen, —NO₂, —OH, —CN, —SF₅,—OSF₅, alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, and alkoxy. Inanother such embodiment, R⁹ is —NO₂. In another such embodiment, R^(N)is phenyl and R⁹ is —NO₂.

In yet another alternative of said immediately preceding embodiment,R^(N) is selected from the group consisting of H, —C(O)CH₃, —S(O)₂CH₃,—C(O)NHCH₃, methyl, benzyl, benzyl substituted with —NO₂, phenyl, andphenyl substituted with —NO₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is:

each R² is independently selected from the group consisting of H,methyl, ethyl, —CH₂OH, —CH₂OCH₃, cyclopropyl, —CF₃, —CHF₂, and —CH₂F;and

R^(N) is selected from any of the alternative embodiments for R^(N)described above.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is:

each R² is independently selected from the group consisting of H,methyl, —CH₂OH, —CF₃, —CHF₂, and —CH₂F; and

R^(N) is selected from any of the alternative embodiments for R^(N)described above.

In an alternative of the two immediately preceding embodiments, R^(N) isselected from the group consisting of H, —C(O)CH₃, —S(O)₂CH₃,—C(O)NHCH₃, methyl, ethyl, propyl, isopropyl, cyclopropyl,—CH₂-cyclopropyl, benzyl, and phenyl,

wherein said benzyl and said phenyl of R^(N) are each optionallyunsubstituted or substituted with R⁹. In one such embodiment, R⁹ isselected from the group consisting of halogen, —NO₂, —OH, —CN, —SF₅,—OSF₅, alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, and alkoxy. Inanother such embodiment, R⁹ is —NO₂. In another such embodiment, R^(N)is phenyl and R⁹ is —NO₂.

In another alternative of said immediately preceding embodiments, R^(N)is selected from the group consisting of H, —C(O)CH₃, —S(O)₂CH₃,—C(O)NHCH₃, methyl, benzyl, benzyl substituted with —NO₂, phenyl, andphenyl substituted with —NO₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is:

each R² is H;

R⁴ is selected from the group consisting of methyl and —CHF₂; and

R^(N) is selected from any of the alternative embodiments for R^(N)described above.

In an alternative of the immediately preceding embodiment, R^(N) isselected from the group consisting of H, —C(O)CH₃, —S(O)₂CH₃,—C(O)NHCH₃, methyl, ethyl, propyl, isopropyl, cyclopropyl,—CH₂-cyclopropyl, benzyl, and phenyl,

wherein said benzyl and said phenyl of R^(N) are each optionallyunsubstituted or substituted with R⁹. In one such embodiment, R⁹ isselected from the group consisting of halogen, —NO₂, —OH, —CN, —SF₅,—OSF₅, alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, and alkoxy. Inanother such embodiment, R⁹ is —NO₂. In another such embodiment, R^(N)is phenyl and R⁹ is —NO₂.

In another alternative of said immediately preceding embodiment, R^(N)is selected from the group consisting of H, —C(O)CH₃, —S(O)₂CH₃,—C(O)NHCH₃, methyl, benzyl, benzyl substituted with —NO₂, phenyl, andphenyl substituted with —NO₂.

Each of the following embodiments may apply to each of the abovealternative embodiments.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridazinyl,pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridazinyl,pyridyl, pyrimidinyl, and pyrazinyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl and pyridyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,

cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —OCH₃, —CH₂OCH₃, methyl,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, —CN, —OCH₃, —CH₂OCH₃, methyl, cyclopropyl,—CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridazinyl,pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl;

m is 0, 1, or 2; and

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,

cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

It shall be understood that the phrase “m is 0 or more” means m is aninteger from 0 up to the number that corresponds to the maximum numberof substitutable hydrogen atoms of the ring to which R^(A) is shownattached.

Thus, in embodiments wherein ring A is a moiety having 4 substitutablehydrogen atoms, m is 0, 1, 2, 3, or 4. In an alternative of suchembodiments wherein ring A is a moiety having 4 substitutable hydrogenatoms, m is 0, 1, 2, or 3. In an alternative of such embodiments whereinring A is a moiety having 4 substitutable hydrogen atoms, m is 0, 1, or2. In an alternative of such embodiments wherein ring A is a moietyhaving 4 substitutable hydrogen atoms, m is 0 or 1. In alternative ofsuch embodiments wherein ring A is a moiety having 4 substitutablehydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 3 substitutablehydrogen atoms, m is 0, 1, 2, or 3. In an alternative of suchembodiments wherein ring A is a moiety having 3 substitutable hydrogenatoms, m is 0, 1, or 2. In an alternative of such embodiments whereinring A is a moiety having 3 substitutable hydrogen atoms, m is 0 or 1.In alternative of such embodiments wherein ring A is a moiety having 3substitutable hydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 2 substitutablehydrogen atoms, m is 0, 1, or 2. In an alternative of such embodimentswherein ring A is a moiety having 2 substitutable hydrogen atoms, m is 0or 1. In alternative of such embodiments wherein ring A is a moietyhaving 2 substitutable hydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 1 substitutablehydrogen atom, m is 0 or 1. In an alternative of such embodimentswherein ring A is a moiety having 1 substitutable hydrogen atoms, m is0.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is selected from the group consisting of lower alkyl and lowerheteroalkyl, wherein said lower alkyl and lower heteroalkyl of R^(L) areeach optionally unsubstituted or substituted with one or more halogen.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is selected from the group consisting of methyl, ethyl, propyl,butyl, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂CH₂OCH₃, —CH₂SCH₃, —CH₂SCH₂CH₃, —CH₂CH₂SCH₃, —CH₂N(CH₃)₂, —CH₂NHCH₃,—CH₂CH₂N(CH₃)₂, —CH₂OCF₃, —CH₂OCHF₂, and —CH₂OCH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R^(L)is selected from the group consisting of methyl, ethyl, —CF₃, —CHF₂,—CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂SCH₃, —CH₂N(CH₃)₂,—CH₂OCF₃, —CH₂OCHF₂, and —CH₂OCH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R^(L)is selected from the group consisting of methyl, ethyl, —CF₃, —CHF₂,—CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCF₃, —CH₂OCHF₂, and —CH₂OCH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein q, L_(B), ring B, p, and R^(B) are each as defined in Formula(I).

In some embodiments, in each of Formulas (I), (I′), (IA), and (IA′):

q is 0. In such embodiments, -L_(B)- is absent; R^(L) is a moiety havingthe formula

and ring B and -L₁- are directly connected as shown:

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—.

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of azetidinyl,benzimidazolyl, benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl,benzoxazoyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of cyclobutyl, cyclopropyl,furanyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl,thiadiazolyl, thiazolyl, and thienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of furanyl, indolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl,thiazolyl, and thienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂,—NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂C H₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl, oxadiazoyl,isoxazoyl, oxazoyl, and pyrrolyl,

-   -   wherein each said phenyl, pyridyl, oxadiazoyl, isoxazoyl,        oxazoyl, and pyrrolyl is optionally substituted with from 1 to 3        substituents independently selected from the group consisting of        F, Cl, —CN, —CH₃, —OCH₃, and —CF₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃),—N(CH₃)₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂C H₃,—C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl,propyl, cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡C—CH₃,—CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—;

ring B is selected from the group consisting of azetidinyl,benzimidazolyl, benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl,benzoxazoyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂,—NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂C H₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl, oxadiazoyl,isoxazoyl, oxazoyl, and pyrrolyl,

-   -   wherein each said phenyl, pyridyl, oxadiazoyl, isoxazoyl,        oxazoyl, and pyrrolyl is optionally substituted with from 1 to 3        substituents independently selected from the group consisting of        F, Cl, CN, —CH₃, —OCH₃, and —CF₃.

In an alternative of the immediately preceding embodiment, q is 0.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—;

ring B is selected from the group consisting of cyclobutyl, cyclopropyl,furanyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl,thiadiazolyl, thiazolyl, and thienyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃),—N(CH₃)₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂C H₃,—C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl,propyl, cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡C—CH₃,—CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In an alternative of the immediately preceding embodiment, q is 0.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and R^(L) is a moiety having the formula

wherein:

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—.

ring B is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡C—CH³, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In an alternative of the immediately preceding embodiment, -L_(B)- is adivalent moiety selected from the group consisting of —CH₂—, —CF₂—, and—CH₂CH₂—.

In another alternative of the immediately preceding embodiment, -L_(B)-is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

q is 0; and R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

It shall be understood that the phrase “p is 0 or more” means p is aninteger from 0 up to the number that corresponds to the maximum numberof substitutable hydrogen atoms of the ring to which R^(B) is shownattached.

Thus, in embodiments wherein ring B is a moiety having 4 substitutablehydrogen atoms, p is 0, 1, 2, 3, or 4. In an alternative of suchembodiments wherein ring B is a moiety having 4 substitutable hydrogenatoms, p is 0, 1, 2, or 3. In an alternative of such embodiments whereinring B is a moiety having 4 substitutable hydrogen atoms, p is 0, 1, or2. In an alternative of such embodiments wherein ring B is a moietyhaving 4 substitutable hydrogen atoms, p is 0 or 1. In alternative ofsuch embodiments wherein ring B is a moiety having 4 substitutablehydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 3 substitutablehydrogen atoms, p is 0, 1, 2, or 3. In an alternative of suchembodiments wherein ring B is a moiety having 3 substitutable hydrogenatoms, p is 0, 1, or 2. In an alternative of such embodiments whereinring B is a moiety having 3 substitutable hydrogen atoms, p is 0 or 1.In alternative of such embodiments wherein ring B is a moiety having 3substitutable hydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 2 substitutablehydrogen atoms, p is 0, 1, or 2. In an alternative of such embodimentswherein ring B is a moiety having 2 substitutable hydrogen atoms, p is 0or 1. In alternative of such embodiments wherein ring B is a moietyhaving 2 substitutable hydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 1 substitutablehydrogen atom, p is 0 or 1. In an alternative of such embodimentswherein ring B is a moiety having 1 substitutable hydrogen atoms, p is0.

In an alternative of each of the embodiments described above, -L₁- is—C(O)NH—.

As noted above, -L₁- (and -L_(B)- when present) represent divalentmoieties. The orientation of such divalent moieties in the formula isthe same as the orientation of the moiety as written. Thus, for example,when R^(L) is the moiety

and -L₁- is a —C(O)NH— group, the moiety

has the formula:

In an alternative of the above embodiments, in each of Formulas (I),(IA), and (IA′), ring A is phenyl, m is 1 or 2, R^(A) is fluoro; -L₁- is—C(O)NH—; ring B is selected from the group consisting of phenyl,pyridyl, and pyrazinyl, p is 0, 1, or 2, and each R^(B) (when present)is independently selected from the group consisting of fluoro, chloro,bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂, —NHC(O)CH₃,—N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂C H₃, —C(O)OCH₃, —C(O)OCH₂CH₃,—C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃,—OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H,—OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In an alternative of the immediately preceding embodiment, each R^(B)group (when present) is independently selected from the group consistingof fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂,—OCH₂F, and —OCH₂CH₂F.

Specific non-limiting examples of compounds of the invention are shownin the table of examples below. While only one tautomeric form of eachcompound is shown in the tables, it shall be understood that alltautomeric forms of the compounds are contemplated as being within thescope of the non-limiting examples.

In another embodiment, 1 to 3 carbon atoms of the compounds of theinvention may be replaced with 1 to 3 silicon atoms so long as allvalency requirements are satisfied.

In another embodiment, there is provided a composition comprising acompound of the invention and a pharmaceutically acceptable carrier ordiluent.

Another embodiment provides a composition comprising a compound of theinvention, either as the sole active agent, or optionally in combinationwith one or more additional therapeutic agents, and a pharmaceuticallyacceptable carrier or diluent. Non-limiting examples of additionaltherapeutic agents which may be useful in combination with the compoundsof the invention include those selected from the group consisting of:(a) drugs that may be useful for the treatment of Alzheimer's diseaseand/or drugs that may be useful for treating one or more symptoms ofAlzheimer's disease, (b) drugs that may be useful for inhibiting thesynthesis AP, (c) drugs that may be useful for treatingneurodegenerative diseases, and (d) drugs that may be useful for thetreatment of type II diabetes and/or one or more symptoms or associatedpathologies thereof.

Non-limiting examples of additional therapeutic agents which may beuseful in combination with the compounds of the invention include drugsthat may be useful for the treatment, prevention, delay of onset,amelioration of any pathology associated with Aβ and/or a symptomthereof. Non-limiting examples of pathologies associated with Aβinclude: Alzheimer's Disease, Down's syndrome, Parkinson's disease,memory loss, memory loss associated with Alzheimer's disease, memoryloss associated with Parkinson's disease, attention deficit symptoms,attention deficit symptoms associated with Alzheimer's disease (“AD”),Parkinson's disease, and/or Down's syndrome, dementia, stroke,microgliosis and brain inflammation, pre-senile dementia, seniledementia, dementia associated with Alzheimer's disease, Parkinson'sdisease, and/or Down's syndrome, progressive supranuclear palsy,cortical basal degeneration, neurodegeneration, olfactory impairment,olfactory impairment associated with Alzheimer's disease, Parkinson'sdisease, and/or Down's syndrome, β-amyloid angiopathy, cerebral amyloidangiopathy, hereditary cerebral hemorrhage, mild cognitive impairment(“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysiscomplications (from β₂ microglobulins and complications arisingtherefrom in hemodialysis patients), scrapie, bovine spongiformencephalitis, and Creutzfeld-Jakob disease, comprising administering tosaid patient at least one compound of the invention, or a tautomer orisomer thereof, or pharmaceutically acceptable salt or solvate of saidcompound or said tautomer, in an amount effective to inhibit or treatsaid pathology or pathologies.

Non-limiting examples of additional therapeutic agents for that may beuseful in combination with compounds of the invention include:muscarinic antagonists (e.g., m₁ agonists (such as acetylcholine,oxotremorine, carbachol, or McNa343), or m₂ antagonists (such asatropine, dicycloverine, tolterodine, oxybutynin, ipratropium,methoctramine, tripitamine, or gallamine)); cholinesterase inhibitors(e.g., acetyl- and/or butyrylchlolinesterase inhibitors such asdonepezil (Aricept®,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride), galantamine (Razadyne®), and rivastigimine (Exelon®);N-methyl-D-aspartate receptor antagonists (e.g., Namenda® (memantineHCl, available from Forrest Pharmaceuticals, Inc.); combinations ofcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists;gamma secretase modulators; gamma secretase inhibitors; non-steroidalanti-inflammatory agents; anti-inflammatory agents that can reduceneuroinflammation; anti-amyloid antibodies (such as bapineuzemab,Wyeth/Elan); vitamin E; nicotinic acetylcholine receptor agonists; CB1receptor inverse agonists or CB1 receptor antagonists; antibiotics;growth hormone secretagogues; histamine H3 antagonists; AMPA agonists;PDE4 inhibitors; GABA_(A) inverse agonists; inhibitors of amyloidaggregation; glycogen synthase kinase beta inhibitors; promoters ofalpha secretase activity; PDE-10 inhibitors; Tau kinase inhibitors(e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); Tauaggregation inhibitors (e.g., Rember®); RAGE inhibitors (e.g., TTP 488(PF-4494700)); anti-Abeta vaccine; APP ligands; agents that upregulateinsulin, cholesterol lowering agents such as HMG-CoA reductaseinhibitors (for example, statins such as Atorvastatin, Fluvastatin,Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin,Simvastatin) and/or cholesterol absorption inhibitors (such asEzetimibe), or combinations of HMG-CoA reductase inhibitors andcholesterol absorption inhibitors (such as, for example, Vytorin®);fibrates (such as, for example, clofibrate, Clofibride, Etofibrate, andAluminium Clofibrate); combinations of fibrates and cholesterol loweringagents and/or cholesterol absorption inhibitors; nicotinic receptoragonists; niacin; combinations of niacin and cholesterol absorptioninhibitors and/or cholesterol lowering agents (e.g., Simcor®(niacin/simvastatin, available from Abbott Laboratories, Inc.); LXRagonists; LRP mimics; H3 receptor antagonists; histone deacetylaseinhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g., PRX-03140 (EpixPharmaceuticals)); 5-HT6 receptor antagonists; mGluR1 receptormodulators or antagonists; mGluR5 receptor modulators or antagonists;mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1inhibitors; agents that can induce Abeta efflux such as gelsolin;Metal-protein attenuating compound (e.g, PBT2); and GPR3 modulators; andantihistamines such as Dimebolin (e.g., Dimebon®, Pfizer).

Another embodiment provides a method of preparing a pharmaceuticalcomposition comprising the step of admixing at least one compound of theinvention, or a tautomer or stereoisomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound, said stereoisomer, or saidtautomer, and a pharmaceutically acceptable carrier or diluent.

Another embodiment provides a method of inhibiting β-secretasecomprising exposing a population of cells expressing β-secretase to atleast one compound of the invention, or a tautomer or stereoisomerthereof, or pharmaceutically acceptable salt or solvate of saidcompound, said stereoisomer, or said tautomer, in an amount effective toinhibit β-secretase. In one such embodiment, said population of cells isin vivo. In another such embodiment, said population of cells is exvivo. In another such embodiment, said population of cells is in vitro.

Additional embodiments in which the compounds of the invention may beuseful include: a method of inhibiting β-secretase in a patient in needthereof. A method of inhibiting the formation of Aβ from APP in apatient in need thereof. A method of inhibiting the formation of Aβplaque and/or Aβ fibrils and/or Aβ oligomers and/or senile plaquesand/or neurofibrillary tangles and/or inhibiting the deposition ofamyloid protein (e.g., amyloid beta protein) in, on or aroundneurological tissue (e.g., the brain), in a patient in need thereof.Each such embodiment comprises administering at least one compound ofthe invention, or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer, in a therapeutically effective amount toinhibit said pathology or condition in said patient.

Additional embodiments in which the compounds of the invention may beuseful include: a method of treating, preventing, and/or delaying theonset of one or more pathologies associated with Aβ and/or one or moresymptoms of one or more pathologies associated with Aβ. Non-limitingexamples of pathologies which may be associated with Aβ include:Alzheimer's Disease, Down's syndrome, Parkinson's disease, memory loss,memory loss associated with Alzheimer's disease, memory loss associatedwith Parkinson's disease, attention deficit symptoms, attention deficitsymptoms associated with Alzheimer's disease (“AD”), Parkinson'sdisease, and/or Down's syndrome, dementia, stroke, microgliosis andbrain inflammation, pre-senile dementia, senile dementia, dementiaassociated with Alzheimer's disease, Parkinson's disease, and/or Down'ssyndrome, progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment, olfactory impairment associatedwith Alzheimer's disease, Parkinson's disease, and/or Down's syndrome,β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebralhemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis,type II diabetes, hemodialysis complications (from β₂ microglobulins andcomplications arising therefrom in hemodialysis patients), scrapie,bovine spongiform encephalitis, and Creutzfeld-Jakob disease, saidmethod(s) comprising administering to said patient in need thereof atleast one compound of the invention, or a tautomer or stereoisomerthereof, or pharmaceutically acceptable salt or solvate of saidcompound, said stereoisomer, or said tautomer, in an amount effective toinhibit said pathology or pathologies.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating Alzheimer's disease, wherein said methodcomprises administering an effective (i.e., therapeutically effective)amount of one or more compounds of the invention (or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer), optionally infurther combination with one or more additional therapeutic agents whichmay be effective to treat Alzheimer's disease or a disease or conditionassociated therewith, to a patient in need of treatment. In embodimentswherein one or more additional therapeutic agents are administered, suchagents may be administered sequentially or together. Non-limitingexamples of associated diseases or conditions, and non-limiting examplesof suitable additional therapeutically active agents, are as describedabove.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating mild cognitive impairment (“MCI”), whereinsaid method comprises administering an effective (i.e., therapeuticallyeffective) amount of one or more compounds of the invention (or atautomer or stereoisomer thereof, or pharmaceutically acceptable salt orsolvate of said compound, said stereoisomer, or said tautomer) to apatient in need of treatment. In one such embodiment, treatment iscommenced prior to the onset of symptoms.

Another embodiment in which the compounds of the invention may be usefulincludes a method of preventing, or alternatively of delaying the onset,of mild cognitive impairment or, in a related embodiment, of preventingor alternatively of delaying the onset of Alzheimer's disease. In suchembodiments, treatment can be initiated prior to the onset of symptoms,in some embodiments significantly before (e.g., from several months toseveral years before) the onset of symptoms to a patient at risk fordeveloping MCI or Alzheimer's disease. Thus, such methods compriseadministering, prior to the onset of symptoms or clinical or biologicalevidence of MCI or Alzheimer's disease (e.g., from several months toseveral yeards before, an effective (i.e., therapeutically effective),and over a period of time and at a frequency of dose sufficient for thetherapeutically effective degree of inhibition of the BACE enzyme overthe period of treatment, an amount of one or more compounds of theinvention (or a tautomer or stereoisomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound, said stereoisomer, or saidtautomer) to a patient in need of treatment.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating Down's syndrome, comprising administeringan effective (i.e., therapeutically effective) amount of one or morecompounds of the invention (or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer) to a patient in need of treatment.

Another embodiment in which the compounds of the invention may be usefulincludes a kit comprising, in separate containers, in a single package,pharmaceutical compositions for use in combination, wherein onecontainer comprises an effective amount of a compound of the invention(or a tautomer or stereoisomer thereof, or pharmaceutically acceptablesalt or solvate of said compound, said stereoisomer, or said tautomer)in a pharmaceutically acceptable carrier, and another container (i.e., asecond container) comprises an effective amount of anotherpharmaceutically active ingredient, the combined quantities of thecompound of the invention and the other pharmaceutically activeingredient being effective to: (a) treat Alzheimer's disease, or (b)inhibit the deposition of amyloid protein in, on or around neurologicaltissue (e.g., the brain), or (c) treat neurodegenerative diseases, or(d) inhibit the activity of BACE-1 and/or BACE-2.

In various embodiments, the compositions and methods disclosed above andbelow wherein the compound(s) of the invention is a compound orcompounds selected from the group consisting of the exemplary compoundsof the invention described below.

In another embodiment, the invention provides for the use of a compoundof the invention, or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer, in the manufacture of a medicament whichmay be useful in: the treatment, the delay of onset, and/or theprevention of one or more Aβ pathologies and/or in the treatment, thedelay of onset, and/or the prevention of one or more symptoms of one ormore Aβ pathologies.

DEFINITIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence the definition of “alkyl” applies to“alkyl” as well as the “alkyl” protion of “hydroxyalkyl”, “haloalkyl”,arylalkyl-, alkylaryl-, “alkoxy” etc.

It shall be understood that, in the various embodiments of the inventiondescribed herein, any variable not explicitly defined in the context ofthe embodiment is as defined in Formula (I). All valences not explicitlyfilled are assumed to be filled by hydrogen.

“Patient” includes both human and non-human animals. Non-human animalsinclude those research animals and companion animals such as mice,primates, monkeys, great apes, canine (e.g., dogs), and feline (e.g.,house cats).

“Pharmaceutical composition” (or “pharmaceutically acceptablecomposition”) means a composition suitable for administration to apatient. Such compositions may contain the neat compound (or compounds)of the invention or mixtures thereof, or salts, solvates, prodrugs,isomers, or tautomers thereof, or they may contain one or morepharmaceutically acceptable carriers or diluents. The term“pharmaceutical composition” is also intended to encompass both the bulkcomposition and individual dosage units comprised of more than one(e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like.

Similarly, the herein-described method of treating a patient byadministering a pharmaceutical composition of the present invention isalso intended to encompass the administration of the afore-said bulkcomposition and individual dosage units.

“Halogen” (or “halo”) means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl andt-butyl.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heteroalkyl” means an alkyl moiety as defined above, having one or morecarbon atoms, for example one, two or three carbon atoms, replaced withone or more heteroatoms, which may be the same or different, where thepoint of attachment to the remainder of the molecule is through a carbonatom of the heteroalkyl radical. Suitable such heteroatoms include O, S,S(O), S(O)₂, and —NH—, —N(alkyl)-. Non-limiting examples include ethers,thioethers, amines, and the like.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. More generally, thesuffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates a divalentmoiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl. “Monocyclic aryl” means phenyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or moresubstituents, which may be the same or different, as defined herein. Theprefix aza, oxa or thia before the heteroaryl root name means that atleast a nitrogen, oxygen or sulfur atom respectively, is present as aring atom. A nitrogen atom of a heteroaryl can be optionally oxidized tothe corresponding N-oxide. “Heteroaryl” may also include a heteroaryl asdefined above fused to an aryl as defined above. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl(which alternatively may be referred to as thiophenyl), pyrimidinyl,pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl,oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term“monocyclic heteroaryl” refers to monocyclic versions of heteroaryl asdescribed above and includes 4- to 7-membered monocyclic heteroarylgroups comprising from 1 to 4 ring heteroatoms, said ring heteroatomsbeing independently selected from the group consisting of N, O, and S,and oxides thereof. The point of attachment to the parent moiety is toany available ring carbon or ring heteroatom. Non-limiting examples ofmonocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridazinyl, pyridoneyl, thiazolyl, isothiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl),imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.

“Cycloalkyl” means a non-aromatic monocyclic or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 3 to about6 carbon atoms. The cycloalkyl can be optionally substituted with one ormore substituents, which may be the same or different, as describedherein. Monocyclic cycloalkyl refers to monocyclic versions of thecycloalkyl moieties described herein. Non-limiting examples of suitablemonocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of multicycliccycloalkyls include[1.1.1]-bicyclopentane, 1-decalinyl, norbomyl,adamantyl and the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contain at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or moresubstituents, which may be the same or different, as described herein.The term “monocyclic cycloalkenyl” refers to monocyclic versions ofcycloalkenyl groups described herein and includes non-aromatic 3- to7-membered monocyclic cycloalkyl groups which contains one or morecarbon-carbon double bonds. Non-limiting examples include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohetpenyl,cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitablemulticyclic cycloalkenyl is norbornylenyl.

“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appearsin a definition of a variable in a general structure described herein,refers to the corresponding N-oxide, S-oxide, or S,S-dioxide.“Heterocyclyl” also includes rings wherein ═O replaces two availablehydrogens on the same carbon atom (i.e., heterocyclyl includes ringshaving a carbonyl group in the ring). Such ═O groups may be referred toherein as “oxo.” An example of such a moiety is pyrrolidinone (orpyrrolidone):

As used herein, the term “monocyclic heterocycloalkyl” refers monocyclicversions of the heterocycloalkyl moities decribed herein and include a4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to4 ring heteroatoms, said ring heteroatoms being independently selectedfrom the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)₂.The point of attachment to the parent moiety is to any available ringcarbon or ring heteroatom. Non-limiting examples of monocyclicheterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam,delta lactam, beta lactone, gamma lactone, delta lactone, andpyrrolidinone, and oxides thereof. Non-limiting examples of loweralkyl-substituted oxetanyl include the moiety:

“Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitableheterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”also includes rings wherein ═O replaces two available hydrogens on thesame carbon atom (i.e., heterocyclyl includes rings having a carbonylgroup in the ring). Example of such moiety is pyrrolidenone (orpyrrolone):

As used herein, the term “monocyclic heterocycloalkenyl” refers tomonocyclic versions of the heterocycloalkenyl moities described hereinand include 4- to 7-membered monocyclic heterocycloalkenyl groupscomprising from 1 to 4 ring heteroatoms, said ring heteroatoms beingindependently selected from the group consisting of N, N-oxide, O, S,S-oxide, S(O), and S(O)₂. The point of attachment to the parent moietyis to any available ring carbon or ring heteroatom. Non-limitingexamples of monocyclic heterocyloalkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, andoxides thereof.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom.

there is no —OH attached directly to carbons marked 2 and 5.

As used herein, the term “multicyclic group” refers to a fused ringsystem comprising two (bicyclic), three (tricyclic), or more fusedrings, wherein each ring of the fused ring system is independentlyselected from the group consisting of phenyl, monocyclic heteroaryl,monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclicheterocycloalkyl, and monocyclic heterocycloalkenyl, as defined above.The point of attachment to the parent moiety is to any available ringcarbon or (if present) ring heteroatom on any of the fused rings. Itshall be understood that each of the following multicyclic groupspictured may be unsubstituted or substituted, as described herein. Onlythe point of attachment to the parent moiety is shown by the wavy line.

The term multicyclic group includes bicyclic aromatic groups.Non-limiting examples of multicyclic groups which are bicyclic aromaticgroups include:

The term multicyclic group thus includes bicyclic heteroaromatic groupscomprising from 1 to 3 ring heteroatoms, each said ring heteroatom beingindependently selected from the group consisting of N, O, and S, S(O),S(O)₂, and oxides of N, O, and S, and oxides thereof.

The term multicyclic group includes saturated bicyclic cycloalkylgroups. Non-limiting examples of multicyclic groups which are saturatedbicyclic cycloalkyl groups include the following:

The term multicyclic group includes partially unsaturated bicycliccycloalkyl groups.

Non-limiting examples of multicyclic groups which comprise partiallyunsaturated bicyclic cycloalkyl groups include the following:

The term multicyclic groups includes partially or fully saturatedbicyclic groups comprising from 1 to 3 ring heteroatoms, each said ringheteroatom is independently selected from the group consisting of N, O,and S, S(O), S(O)₂, and oxides of N, O, and S.

The term multicyclic group includes aromatic tricyclic groups,cycloalkyl tricyclic groups, as well as heteroaromatic and partially andfully saturated tricyclic groups. For tricyclic groups comprising ringheteroatoms, said tricyclic groups comprise one or more (e.g., from 1 to5) ring heteroatoms, wherein each said ring heteroatom is independentlyselected from N, O, and S, S(O), S(O)₂, and oxides of N, O, and S:

“Arylalkyl” (or “aralkyl”) means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl. The term (and similar terms) may bewritten as “arylalkyl-” (or as “-alkyl-aryl”) to indicate the point ofattachment to the parent moiety. Similarly, “heteroarylalkyl”,“cycloalkylalkyl”, “cycloalkenylalkyl”, “heterocycloalkylalkyl”,“heterocycloalkenylalkyl”, etc., mean a heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, etc. as describedherein bound to a parent moiety through an alkyl group. Preferred groupscontain a lower alkyl group. Such alkyl groups may be straight orbranched, unsubstituted and/or substituted as described herein.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl,adamantylpropyl, and the like.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclylalkyl” (or “heterocycloalkylalkyl”) means a heterocyclylmoiety as defined above linked via an alkyl moiety (defined above) to aparent core. Non-limiting examples of suitable heterocyclylalkylsinclude piperidinylmethyl, piperazinylmethyl and the like.

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

Any of the foregoing functional groups may be unsubstituted orsubstituted as described herein. The term “substituted” means that oneor more hydrogens on the designated atom is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency under the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. By “stable compound’ or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, arylfused cycloalkylalkyl- moiety or the like includessubstitution on any ring portion and/or on the alkyl portion of thegroup.

When a variable appears more than once in a group, e.g., R⁶ in —N(R⁶)₂,or a variable appears more than once in a structure presented herein,the variables can be the same or different.

The line

, as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)- stereochemistry. For example:

means containing both and

The wavy line

as used herein, indicates a point of attachment to the rest of thecompound. Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

“Oxo” is defined as a oxygen atom that is double bonded to a ring carbonin a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or otherring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system. As well known in the art, a bonddrawn from a particular atom wherein no moiety is depicted at theterminal end of the bond indicates a methyl group bound through thatbond to the atom, unless stated otherwise. For example:

In another embodiment, the compounds of the invention, and/orcompositions comprising them, are present in isolated and/or purifiedform. The term “purified”, “in purified form” or “in isolated andpurified form” for a compound refers to the physical state of saidcompound after being isolated from a synthetic process (e.g. from areaction mixture), or natural source or combination thereof. Thus, theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound (or atautomer or stereoisomer thereof, or pharmaceutically acceptable salt orsolvate of said compound, said stereoisomer, or said tautomer) afterbeing obtained from a purification process or processes described hereinor well known to the skilled artisan (e.g., chromatography,recrystallization and the like), in sufficient purity to be suitable forin vivo or medicinal use and/or characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

Those skilled in the art will recognize those instances in which thecompounds of the invention may be converted to prodrugs and/or solvates,another embodiment of the present invention. A discussion of prodrugs isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems (1987) 14 of the A.C.S. Symposium Series, and in BioreversibleCarriers in Drug Design, (1987) Edward B. Roche, ed., AmericanPharmaceutical Association and Pergamon Press. The term “prodrug” meansa compound (e.g, a drug precursor) that is transformed in vivo to yielda compound of the invention or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (e.g., by metabolic or chemical processes), such as,for example, through hydrolysis in blood. A discussion of the use ofprodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms where they exist. “Solvate”means a physical association of a compound of the invention with one ormore solvent molecules. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

Those skilled in the art will recognize those instances in which thecompounds of the invention may form salts. In such instances, anotherembodiment provides pharmaceutically acceptable salts of the compoundsof the invention. Thus, reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes any of thefollowing: acidic salts formed with inorganic and/or organic acids, aswell as basic salts formed with inorganic and/or organic bases. Inaddition, when a compound of the invention contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare also potentially useful. Salts of the compounds of the invention maybe formed by methods known to those of ordinary skill in the art, forexample, by reacting a compound of the invention with an amount of acidor base, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts which may be useful include acetates,ascorbates, benzoates, benzenesulfonates, bisulfates, borates,butyrates, citrates, camphorates, camphorsulfonates, fumarates,hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,methanesulfonates, naphthalenesulfonates, nitrates, oxalates,phosphates, propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates,) and the like.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered as potentially useful alternatives to the freeforms of the corresponding compounds for purposes of the invention.

Another embodiment which may be useful includes pharmaceuticallyacceptable esters of the compounds of the invention. Such esters mayinclude the following groups: (1) carboxylic acid esters obtained byesterification of the hydroxy groups, in which the non-carbonyl moietyof the carboxylic acid portion of the ester grouping is selected fromstraight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

As mentioned herein, under certain conditions the compounds of theinvention may form tautomers. Such tautomers, when present, compriseanother embodiment of the invention. It shall be understood that alltautomeric forms of such compounds are within the scope of the compoundsof the invention. For example, all keto-enol and imine-enamine forms ofthe compounds, when present, are included in the invention. Thus, acompounds of the invention conforming to the formula:

and its tautomer, which can be depicted as:

are both contemplated as being within the scope of the compounds of theinvention. As noted above, while only one said tautomeric form of eachcompound is shown in the tables, it shall be understood that alltautomeric forms of the compounds are contemplated as being within thescope of the non-limiting example compounds of the invention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Where various stereoisomers of the compounds of the invention arepossible, another embodiment provides for diastereomeric mixtures andindividual enantiomers of the compounds of the invention. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods well known tothose skilled in the art, such as, for example, by chromatography and/orfractional crystallization. Enantiomers can be separated by convertingthe enantiomeric mixture into a diastereomeric mixture by reaction withan appropriate optically active compound (e.g., chiral auxiliary such asa chiral alcohol or Mosher's acid chloride), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. Also, some of thecompounds of the invention may be atropisomers (e.g., substitutedbiaryls) and are considered as part of this invention. Enantiomers canalso be separated by use of chiral HPLC column.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the compounds of the invention (including those of thesalts, solvates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated as embodiments within the scope of this invention, as arepositional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (Forexample, if a compound of the invention incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

Another embodiment which may be useful include isotopically-labelledcompounds of the invention. Such compounds are identical to thoserecited herein, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and³⁶Cl, respectively.

In the compounds of the invention, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the invention. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundsof the invention can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the schemes and examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Another embodiment provides suitable dosages and dosage forms of thecompounds of the invention. Suitable doses for administering compoundsof the invention to patients may readily be determined by those skilledin the art, e.g., by an attending physician, pharmacist, or otherskilled worker, and may vary according to patient health, age, weight,frequency of administration, use with other active ingredients, and/orindication for which the compounds are administered. Doses may rangefrom about 0.001 to 500 mg/kg of body weight/day of the compound of theinvention. In one embodiment, the dosage is from about 0.01 to about 25mg/kg of body weight/day of a compound of the invention, or apharmaceutically acceptable salt or solvate of said compound. In anotherembodiment, the quantity of active compound in a unit dose ofpreparation may be varied or adjusted from about 1 mg to about 100 mg,preferably from about 1 mg to about 50 mg, more preferably from about 1mg to about 25 mg, according to the particular application. In anotherembodiment, a typical recommended daily dosage regimen for oraladministration can range from about 1 mg/day to about 500 mg/day,preferably 1 mg/day to 200 mg/day, in two to four divided doses.

When used in combination with one or more additional therapeutic agents,the compounds of this invention may be administered together orsequentially. When administered sequentially, compounds of the inventionmay be administered before or after the one or more additionaltherapeutic agents, as determined by those skilled in the art or patientpreference.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange.

Accordingly, another embodiment provides combinations comprising anamount of at least one compound of the invention, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof, and an effectiveamount of one or more additional agents described above.

Another embodiment provides for pharmaceutically acceptable compositionscomprising a compound of the invention, either as the neat chemical oroptionally further comprising additional ingredients. For preparingpharmaceutical compositions from the compounds of the invention, inert,pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, dispersible granules,capsules, cachets and suppositories. The powders and tablets may becomprised of from about 5 to about 95 percent active ingredient.Suitable solid carriers are known in the art, e.g., magnesium carbonate,magnesium stearate, talc, sugar or lactose. Tablets, powders, cachetsand capsules can be used as solid dosage forms suitable for oraladministration. Examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions may be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18^(th) Edition,(1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.Non-limiting examples which may be useful include water orwater-propylene glycol solutions for parenteral injection or addition ofsweeteners and opacifiers for oral solutions, suspensions and emulsions.Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

Another embodiment which may be useful includes compositions comprisinga compound of the invention formulated for transdermal delivery. Thetransdermal compositions can take the form of creams, lotions, aerosolsand/or emulsions and can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose.

Other embodiment which may be useful includes compositions comprising acompound of the invention formulated for subcutaneous delivery or fororal delivery. In some embodiments, it may be advantageous for thepharmaceutical preparation compring one or more compounds of theinvention be prepared in a unit dosage form. In such forms, thepreparation may be subdivided into suitably sized unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose. Each of the foregoingalternatives, together with their corresponding methods of use, areconsidered as included in the various embodiments of the invention.

PREPARATIVE EXAMPLES

Compounds of the invention can be made using procedures known in theart. The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable. Reactions may involve monitoring for consumption of startingmaterial, and there are many methods for such monitoring, including butnot limited to thin layer chromatography (TLC) and liquid chromatographymass spectrometry (LCMS), and those skilled in the art will recognizethat where one method is specified, other non-limiting methods may besubstituted.

Techniques, solvents and reagents may be referred to by theirabbreviations as follows:

Acetic acid: AcOH

Acetonitrile: MeCN 35

Aqueous: aq. Grams: g

Benzyl: Bn

tert-Butyl: t-Bu or tBu

Centimeters: cm

3-Chloroperoxybenzoic acid: mCPBA

Dichloromethane: DCM Diethylamine: DEA

Diisopropylamine: iPr₂NH or DIPADiisopropylethylamine: DIEA or iPr₂Net

4-Dimethylaminopyridine: DMAP Dimethylformamide: DMF Dimethylsulfoxide:DMSO

Diphenylphosphoryl azide: DPPAEther or diethyl ether: Et₂O

Ethyl: Et

Ethyl acetate: AcOEt, EtOAc, or EA

Example: Ex. Grams: g

O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate:

HATU Hexanes: hex

High performance liquid chromatography:

HPLC Hydroxybenzotriazole: HOBt Inhibition: Inh.

Liquid chromatography mass

Lithium Hexamethyldisilazide: LHMDS Spectrometry: LCMS

Methanesulfonyl chloride: MeSO₂Cl

Methanol: MeOH

Methyl t-butyl ether: MTBEMethyl iodide: MeIMethyl magnesium bromide: MeMgBr

Microliters: μl or μL Micrometer: μm Milligrams: mg Milliliters: mL

Millimoles: mmol

Minutes: min

n-Butyllithium: nBuLi or n-BuLiNuclear magnetic resonance spectroscopy:

NMR Number: no. or No.

Para-methoxy benzyl: PMBPetroleum ether: PE

Polymethylhydrosiloxane: PMHS

Retention time: t_(R) or Ret. Time

Reverse Phase: RP

Room temperature (ambient, about 25° C.):

rt or RT

tert-Butoxycarbonyl: t-Boc or Boc

Supercritical Fluid Chromatography: SFC

Temperature: temp.

Tetrahydrofuran: THF Triethylamine: Et₃N or TEA Trimethylsilyl: TMS

2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide: T3P

Volume: v Method A

Intermediate A2

(R,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide(Method A) Step 1:(R,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide

To a solution of acetophenone A1 (115 g, 628 mmol) in anhydrous THF (900mL) was added (R)-t-butylsulfinimde (83.7 g, 691 mmol, 1.1 eq) andTi(OEt)₄ (315 g, 1.38 mol). The resultant solution was heated to refluxfor 20 hr. The solution was then cooled to RT and poured onto ice (3kg). The resultant mixture was stirred for 20 min. then filtered. Theorganic layer washed with brine. The filter cake was washed with CH₂Cl₂(3×). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by silica gelchromatography (15% EtOAc/heptane) to afford the title compound A2.

Method Aa

Intermediate Aa5

5-cyano-3-cyclopropylpicolinic acid (Method Aa) Step 1: tert-butyl5-bromo-3-chloropicolinate

To a solution of 5-bromo-3-chloropicolinic acid (5.0 g, 21 mmol) in THF(100 mL) at room temperature was added (Boc)₂O (9.2 g, 42 mmol) followedby 4-dimethylaminopyridine (0.8 g, 6.3 mmol). The reaction was stirredfor 2 days and poured into saturated aqueous NH₄Cl. The mixture wasextracted with DCM. The combined organic layers were dried (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (1 column volume of hexanes and then 0-20% EtOAc/hex)to provide the title compound Aa2.

Step 2: tert-butyl 3-chloro-5-cyanopicolinate

To a microwave vial was added tetrakis(triphenylphosphine)palladium(0)(0.20 g, 0.17 mmol), dicyanozinc (0.44 g, 3.8 mmol), and Aa2 (1.0 g, 3.4mmol). The vial was evacuated and DMF (17 mL) was added. The mixture wasdegassed by evacuating and backfilling with nitrogen gas. The vial wascapped and the reaction was warmed to 120° C. and stirred for 40minutes.

The reaction was cooled to room temperature and added to saturatedaqueous NH₄Cl. The mixture was extracted with ether and EtOAc. Thecombined organic layers were dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography (hexanes(2 column volumes), then 0-20% EtOAc/hex (8 column volumes)) to providethe title compound Aa3.

Step 3: tert-butyl 5-cyano-3-cyclopropylpicolinate

To a microwave vial was added Aa3 (0.098 g, 0.41 mmol), cesium carbonate(0.40 g, 1.2 mmol), potassium cyclopropyltrifluoroborate (0.073 g, 0.49mmol), and[(di-(1-adamantyl)-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II)chloride(0.028 g, 0.04 mmol). Toluene (3.7 mL) and water (0.37 mL) were addedand the reaction vessel was degassed and backfilled with nitrogen (3×).The reaction was capped and heated in a microwave for 3 h at 120° C. Thereaction was cooled to room temperature and water was added. The mixturewas extracted with EtOAc. The combined organic layers were washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by preparative TLC (Silica Gel, 1000 micron: 20%EtOAc/hex) to provide the title compound Aa4.

Step 4: 5-cyano-3-cyclopropylpicolinic acid

To Aa4 (0.04 g, 0.17 mmol) in DCM (2 mL) was added TFA (3 mL). Thereaction was stirred for 18 h and then concentrated in vacuo. Theresidue was triturated with ether and concentrated in vacuo to providethe title compound Aa5

Method Ab

INTERMEDIATE Ab6

5-cyano-3-(difluoromethyl)picolinic acid (Method Ab) Step 1:5-bromo-3-formylpicolinic acid

To n-butyllithium (2.5M in hexane, 12 mL, 30 mmol) in THF (40 mL) at−78° C. was added a solution of 3,5-dibromopicolinic acid (4.0 g, 14mmol) in THF (60 mL) over 30 minutes. The reaction was stirred at −78°C. for 1 hour after which DMF (11 mL, 144 mmol) was added dropwise. Thecold bath was allowed to expire while stirring for 12 h. Water was addedfollowed by IN HCl (30 mL). The pH was adjusted to pH 3-4 using IN NaOH.The solution was extracted with EtOAc while maintaining a pH of 3 to 4.The combined organic layers were washed with water and brine, dried(MgSO₄), filtered, and concentrated in vacuo to provide the titlecompound Ab2 that was carried on directly.

Step 2: methyl 5-bromo-3-formylpicolinate

To Ab2 (1.9 g, 8.3 mmol) in diethyl ether (32 mL) and MeOH (11 mL) atroom temperature was added TMS-diazomethane (2.0M in ether, 5.4 mL, 11mmol) dropwise until the yellow color persisted. The reaction wasconcentrated in vacuo to provide a residue that was purified by silicagel chromatography (EtOAc/hex) to provide the title compound Ab3 thatwas used immediately in the next step.

Step 3: methyl 5-bromo-3-(difluoromethyl)picolinate

To Ab3 (0.42 g, 1.7 mmol) in DCM (17 mL) at room temperature was addeddiethylamino sulfur trifluoride dropwise over 3 minutes. The reactionwas stirred at room temperature for 14 h and then poured into saturatedNaHCO₃. The mixture was extracted with DCM. The combined organic layerswere washed with brine, dried (MgSO₄), filtered, and concentrated invacuo to provide the title compound Ab4.

Step 4: methyl 5-cyano-3-(difluoromethyl)picolinate

Ab4 (0.33 g, 1.2 mmol), zinc cyanide (0.16 g, 1.4 mmol), andtetrakis(triphenylphosphine)palladium(0), were combined in a microwavereaction vial under nitrogen. DMF was added and the reaction wasdegassed by evacuating under vacuum and backfilling with nitrogen (3×).The reaction was heated in a microwave reactor at 120° C. for 10minutes. After cooling to room temperature, the reaction was added towater. The mixture was extracted with EtOAc. The combined organic layerswere washed with water and brine, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (EtOAc/hex) to provide the title compound Ab5.

Step 5: 5-cyano-3-(difluoromethyl)picolinic acid

To Ab5 (0.16 g, 0.75 mmol) in THF (6 mL) at room temperature was addedpotassium trimethylsilanoate (0.32 g, 2.2 mmol) in one portion. After 5minutes the reaction was quenched by adding IN HCl (4 mL). The mixturewas extracted with EtOAc. The combined organic layers were washed withbrine, dried (MgSO₄), filtered, and concentrated in vacuo to provide thetitle compound Ab6.

Method Ac

INTERMEDIATE Ac11

(R)-tert-butyl (3-(5-amino-2-fluorophenyl)-3,9-dimethyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undecan-5-ylidene)carbamate (Method Ac) STEP1: tert-butyl 4-cyanopiperidine-1-carboxylate

To a solution of piperidine-4-carbonitrile (10 g, 90.91 mmol) indichloromethane (100 mL) was added di-tert-butyl dicarbonate (21.8 g,100.0 mmol) and triethylamine (18.9 mL, 136.36 mmol). The resultantsolution was stirred at room temperature overnight. The reaction mixturewas diluted with water and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by silica gelchromatography (10-20% ethyl acetate in petroleum ether) to obtain thetitle compound Ac2.

STEP 2: tert-butyl 4-cyano-4-(methylthio)piperidine- 1-carboxylate

To a solution of Ac2 (12 g, 57.14 mmol) in tetrahydrofuran (120 mL) at−78° C. was added LiHMDS (62.83 mL, 62.85 mmol, 1M Solution intetrahydrofuran) dropwise. The reaction mixture was stirred for 30 minat −78° C. A solution of dimethyldisulfide (5.3 mL, 57.14 mmol) intetrahydrofuran (10 mL) was added to the reaction mixture and thereaction mixture stirred for 3 h at −78° C. The reaction mixture wasquenched with a saturated NH₄Cl solution (200 mL) and the productextracted with ethyl acetate. The combined organic layer was washed withwater and brine, dried over anhydrous Na₂SO₄ and concentrated to yieldthe crude product. The crude product was purified by silica gelchromatography (20% ethyl acetate in petroleum ether) to yield the titlecompound Ac3.

STEP 3: tert-butyl 4-cyano-4-(methylsulfonyl)piperidine- 1-carboxylate

To a stirred solution of Ac3 (9 g, 35.1 m mol) in methanol/water mixture(100 mL) at 0° C. was added Oxone (43.1 g, 70.2 mmol) portion wise. Thereaction mixture was stirred at room temperature for 5 h. The reactionmixture was quenched with excess water and extracted withdichloromethane. The combined organic layers were washed with water andbrine, dried over anhydrous Na₂SO₄ and concentrated to yield the titlecompound Ac4 which was taken to the next step without furtherpurification.

STEP 4: 4-(methylsulfonyl)piperidine-4-carbonitrile

To a solution of Ac4 (5 g, 17.33 mmol) in dichloromethane (70 mL), wasadded trifluoroacetic acid (6 mL) at 0° C. and the reaction was allowedto attain room temperature and stirred for 4 h. The reaction mixture wasconcentrated under reduced pressure. The residue was then adjusted to pH8 with the addition of saturated NaHCO₃ solution. The aqueous layer wasextracted with dichloromethane. The organic layers separated were washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated toafford the title compound Ac5 which was taken to the next step withoutfurther purification.

STEP 5: 1-methyl-4-(methylsulfonyl)piperidine-4-carbonitrile

To a stirred solution of Ac5 (2.4 g, 12.74 mmol) in 1,2-dichloroethaneat room temperature was added formaldehyde (10 mL, 37% aqueoussolution), acetic acid (2 mL) and the reaction mixture was stirred atroom temperature for 1 h. Sodium triacetoxyborohydride (5.4 g, 25.49mmol) was added and stirring was continued for 16 h. The reactionmixture was quenched with saturated NaHCO₃ solution, and the aqueouslayer was extracted with dichloromethane. The combined organic layerswere washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated to afford the crude product. The crude product was purifiedby silica gel chromatography (3-5% methanol in dichloromethane) to yieldthe title compound Ac6.

STEP 6:(R)—N—((R)-1-((4-cyano-1-methylpiperidin-4-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide

To a solution of Ac6 (1.9 g, 6.80 mmol) in tetrahydrofuran (20 mL) at−78° C. was added n-BuLi (4.2 mL, 6.80 mmol, 1.6M in hexane) dropwise.The reaction mixture was stirred for 30 min at −78° C. The solution ofA2 (1.3 g, 4.53 mmol) in tetrahydrofuran (10 mL) was added to thereaction mixture and stirred for 3.5 h at −78° C. The reaction mixturewas quenched with saturated NH₄Cl solution (20 mL) and the productextracted with ethyl acetate. The combined organic layer was washed withwater and brine, dried over anhydrous Na₂SO₄ and concentrated to yieldthe crude product. The crude product was purified by silica gelchromatography (5% methanol in dichloromethane) to yield the titlecompound Ac7.

STEP 7:(R)-4-((2-amino-2-(2-fluoro-5-nitrophenyl)propyl)sulfonyl)-1-methylpiperidine-4-carbonitrile

To a solution of the Ac7 (1.3 g, 3.38 mmol) in dichloromethane (20 mL)was added a solution of 4M HCl in dioxane (3 mL). The resultant solutionwas stirred at room temperature for 1 h. The solution was concentratedto afford the crude product. The residue was then adjusted to pH 8 withthe addition of saturated NaHCO₃ solution. The aqueous layer wasextracted with dichloromethane. The combined organic layers were washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated toafford the title compound Ac8 which was taken to the next step withoutfurther purification.

STEP 8:(R)-3-(2-fluoro-5-nitrophenyl)-5-imino-3,9-dimethyl-1-thia-4,9-diazaspiro[5.5]undecane1,1-dioxide

To a slurry of the amine Ac8 (1 g, 2.60 mmol) in ethanol (10 mL) wasadded copper chloride (421 mg, 4.26 mmol). The resultant mixture wasrefluxed for 16 h. The mixture was concentrated to afford the crudeproduct. The residue was then adjusted to pH 8 with the addition ofsaturated 10% NaOH solution. The aqueous layer was extracted withdichloromethane. The organic layers separated were washed with water andbrine and dried over anhydrous Na₂SO₄ and concentrated to afford thetitle compound Ac9 which was taken to the next step without furtherpurification.

STEP 9:(R)-tert-butyl(3-(2-fluoro-5-nitrophenyl)-3,9-dimethyl-1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undecan-5-ylidene)carbamate

To a solution of Ac9 (1 g, 2.60 mmol) in dichloromethane (10 mL) wasadded Boc₂O (0.62 mL, 2.86 mmol) and triethylamine (0.54 mL, 3.90 mmol).The resultant solution was stirred at room temperature overnight. Thesolution was diluted with water and extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, and concentrated. The crude product was purified by silica gelchromatography (5% methanol in dichloromethane) to obtain the titlecompound Ac10.

STEP 10:(R)-tert-butyl(3-(5-amino-2-fluorophenyl)-3,9-dimethyl-1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undecan-5-ylidene)carbamate

A solution of Ac10 (500 mg, 1.03 mmol) in methanol (10 mL) was degassedby bubbling nitrogen through the solution for 5 min. To this solutionwas added Pd/C (20% w/w, 50% H₂O, 100 mg). The resulting mixture wasstirred at room temperature under a hydrogen balloon for 6 h. Thereaction mixture was filtered through celite and concentrated to affordthe title compound Ac11 which was taken to the next step without furtherpurification.

Method Ad

INTERMEDIATE Ad5

(R)-tert-butyl7-(5-amino-2-fluorophenyl)-9-((tert-butoxycarbonyl)imino)-7-methyl-5-thia-2,8-diazaspiro[3.5]nonane-2-carboxylate5,5-dioxide (Method Ad) Step 1: tert-butyl3-cyano-3-(((R)-2-((R)-1,1-dimethylethylsulfinamido)-2-(2-fluoro-5-nitrophenyl)propyl)sulfonyl)azetidine-1-carboxylate

To B2 (3.0 g, 11.5 mmol) in THF (45 mL) at −78° C. was added n-BuLi(2.5M in hexane, 5.1 mL, 12.7 mmol) and the reaction stirred for 1 h. ToA2 (6.6 g, 23.1 mmol) in toluene (12 mL) at −78° C. was addedtrimethylaluminum (2.0M in toluene, 12.8 mL, 25.6 mmol). The mixture wasstirred for 5 minutes at −78° C. after which the anion solution wasadded over 15 minutes. After stirring the mixture for 1.5 h at −78° C.,saturated aqueous Rochelle's salt was added and the mixture was allowedto warm to room temperature. The solid was filtered off and the filtratewas extracted with EtOAc. The combined organic layers were washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo. Thecrude material was purified by silica gel chromatography (0-50%EtOAc/hex over 30 minutes) to provide the title compound Ad1.

Step 2:(R)-3-((2-amino-2-(2-fluoro-5-nitrophenyl)propyl)sulfonyl)azetidine-3-carbonitrile

To Ad1 (2.1 g, 3.9 mmol) in MeOH (13 mL) at room temperature was addedHCl in dioxane (4.0M, 5.8 mL, 23 mmol). The reaction was stirred at roomtemperature for 2 h and then concentrated in vacuo. The crude solid wastriturated with ether and then filtered, washing with ether. The solidwas then taken up into DCM and basified to -pH 10 with saturated aqueousNaHCO₃. The mixture was extracted with DCM. The combined organic layerswere washed with brine, dried (MgSO₄), filtered, and concentrated invacuo to provide the title compound Ad2.

Step 3:(R)-7-(2-fluoro-5-nitrophenyl)-9-imino-7-methyl-5-thia-2,8-diazaspiro[3.5]nonane5,5-dioxide

To Ad2 (1.3 g, 3.8 mmol) in toluene (25 mL) at room temperature wasadded trimethylaluminum (2.0M in toluene, 2.9 mL, 5.7 mmol). Theheterogeneous solution was warmed to 50° C. and stirred for 2 h. Thereaction was cooled to room temperature and saturated aqueous Rochelle'ssalt was added [gas evolution]. Water was added and the mixture wasextracted with EtOAc. The combined organic layers were washed with waterand brine, dried (MgSO₄), filtered, and concentrated in vacuo to providethe title compound Ad3 that was carried on directly to the next step.

Step 4: (R)-tert-butyl9-((tert-butoxycarbonyl)imino)-7-(2-fluoro-5-nitrophenyl)-7-methyl-5-thia-2,8-diazaspiro[3.5]nonane-2-carboxylate5,5-dioxide

To Ad3 (0.76 g, 2.2 mmol) in DCM (7 mL) at room temperature was added(Boc)₂O (1.9 g, 8.9 mmol) followed by DMAP (0.03 g, 0.22 mmol). Themixture was stirred for 18 h at room temperature. The reaction wasloaded directly onto a silica gel column and purified eluting with 0-30%EtOAc/hex over 30 minutes to provide the title compound Ad4.

Step 5: (R)-tert-butyl7-(5-amino-2-fluorophenyl)-9-((tert-butoxycarbonyl)imino)-7-methyl-5-thia-2,8-diazaspiro[3.5]nonane-2-carboxylate5,5-dioxide

To Ad4 (0.61 g, 1.1 mmol) in THF (6 mL) at room temperature was addedPMHS (0.29 mL, 1.1 mmol), potassium fluoride (0.13 g, 2.3 mmol) in water(1.4 mL), and palladium (II) acetate (0.013 g, 0.06 mmol) [gasevolution]. Stirred at room temperature for 2 hours. Added EtOAc andfiltered through a plug of neutral alumina (bottom) and Celite (top)washing with EtOAc. The filtrate was washed with water and brine, dried(MgSO₄), filtered, and concentrated in vacuo. The residue was purifiedby silica gel chromatorgraphy (0-35% EtOAc/hex over 30 minutes) toprovide the title compound Ad5.

Method B

Example 1

(R)-5-cyano-N-(4-fluoro-3-(9-imino-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)picolinamide(Method B) Step 1: tert-butyl 3-cyano-3-(methylsulfonyl)azetidine-1-carboxylate

To B1 (4.0 g, 22 mmol) and dimethyldisulfide (2.5 mL, 27 mmol) in THF(88 mL) at −78° C. was added LHMDS (1.0M in THF, 27 mL, 27 mmol)dropwise. The reaction was stirred at -78° C. for 2 h and then saturatedNH₄Cl(aq) was added and the mixture was allowed to warm to roomtemperature. The mixture was extracted with EtOAc. The combined organiclayers were washed with water and brine, dried (MgSO₄), filtered, andconcentrated in vacuo to provide an oil that was used directly in thenext step.

The oil was taken up into MeOH (88 mL) and Oxone (27.0 g, 44 mmol) inwater (88 mL) was added at room temperature. The heterogeneous mixturewas stirred at room temperature for 16 h. Water was added and themixture was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography (0-50%EtOAc/hex over 35 minutes) to provide the title compound B2.

Step 2: 1-methyl-3-(methylsulfonyl)azetidine-3-carbonitrile

To B2 (6.5 g, 25 mmol) in DCM (83 mL) was added TFA (19 mL, 250 mmol).The reaction was stirred at room temperature for 1 h and thenconcentrated in vacuo. The residue was used directly in the next stepwithout further purification.

To the residue in acetonitrile (83 mL) was added aqueous formaldehyde(37% w/v, 5.6 mL, 75 mmol) and sodium triacetoxyborohydride (15.9 g, 75mmol). The reaction was stirred at room temperature for 18 h and thenconcentrated in vacuo. The residue was taken up into EtOAc and washedwith saturated aq. NaHCO₃. The aqueous layer was extracted with EtOAcand the combined organic layers were washed with water and brine, dried(MgSO₄), filtered, and concentrated in vacuo to provide the titlecompound B3.

Step 3: (R)—N—((R)-1-((3-cyano-1-methylazetidin-3-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide

To B3 (4.1 g, 23 mmol) in THF (93 mL) at −78° C. was added n-BuLi (2.5Min hexane, 10.2 mL, 26 mmol). The resultant mixture was stirred at −78°C. for 1 h. To A2 (13.3 g, 46.5 mmol) in toluene (25 mL) at −78° C. wasadded trimethylaluminum (2M in toluene, 25.6 mL, 51.1 mmol). Afterstirring for 5 minutes, the solution was added to the anion solutionover 25 minutes. The resultant mixture was stirred at −78° C. for 2.5 h.Saturated aq. NH₄Cl (60 mL) and saturated aqueous Rochelle's salt (30mL) were added and the mixture allowed to warm to room temperature. Themixture was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography (0-100%EtOAc/hex over 25 minutes) to provide a residue that was furtherpurified by SFC (Chiralpak IC, 30×250 mm, MeOH/CO₂, 70 mL/min, 140 bar,388 mg/mL in MeOH, 35° C., 220 nm) to provide the title compound B4.

Step 4:(R)-3-((2-amino-2-(2-fluoro-5-nitrophenyl)propyl)sulfonyl)-1-methylazetidine-3-carbonitrile

To B4 (4.0 g, 8.7 mmol) in MeOH (43 mL) was added HCl (4.0M in dioxane,21.7 mL, 87 mmol) at room temperature. The reaction was stirred for 1.5h and then concentrated in vacuo. The residue was suspended in ether andfiltered while washing with ether. The solid residue was taken up intoDCM and stirred with saturated NaHCO₃. The mixture was extracted withDCM. The combined organic layers were washed with brine, dried (MgSO₄),filtered, and concentrated in vacuo to provide the title compound B5.

Step 5:(R)-7-(2-fluoro-5-nitrophenyl)-9-imino-2,7-dimethyl-5-thia-2,8-diazaspiro[3.5]nonane5,5-dioxide

To B5 (3.1 g, 8.7 mmol) in toluene (87 mL) at 0° C. was addedtrimethylaluminum (2.0M in toluene, 4.8 mL, 9.6 mmol). The reaction wasallowed to warm to room temperature and then warmed to 75° C. Thereaction was stirred for 18 h. To the cooled reaction was addedsaturated aqueous Rochelle's salt (10 mL). The mixture was stirred atroom temperature for 5 minutes and then extracted with EtOAc. Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and concentrated in vacuo to provide the title compound B6 that was useddirectly in the next step.

Step 6:(R)-di-tert-butyl(7-(2-fluoro-5-nitrophenyl)-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-8-en-9-yl)imidodicarbonate

To B6 (2.8 g, 7.9 mmol) in DCM (26 mL) at room temperature was added(Boc)₂O (2.6 g, 12 mmol). The reaction was stirred at room temperaturefor 16 h. The reaction mixture was concentrated in vacuo. The residuewas purified by silica gel chromatography (0-60% EtOAc/hex over 35minutes) to provide B7.

Step 7:(R)-di-tert-butyl(7-(5-amino-2-fluorophenyl)-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]non-8-en-9-yl)imidodicarbonate

To B7 (0.70 g, 1.26 mmol) in THF (6.3 mL) was added aqueous potassiumfluoride (0.15 g, 2.52 mmol in water (2.5 mL)), and PMHS (0.32 mL, 1.26mmol). Nitrogen was bubbled through the reaction for 5 minutes afterwhich Pd(OAc)₂ (14 mg, 0.06 mmol) was added. The reaction was stirred atroom temperature for 2 h. EtOAc was added to the reaction mixture andthe mixture was stirred for 5 minutes. The aqueous layer was extractedwith EtOAc and the combined organic layers were filtered through a plugcontaining Celite on the top and neutral alumina on the bottom. Thefiltrate was concentrated in vacuo and purified by silica gelchromatography (0-100% EtOAc/hex over 25 minutes) to provide B8.

Step 8:(R)-Di-tert-butyl(7-(5-(5-cyanopicolinamido)-2-fluorophenyl)-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]non-8-en-9-yl)imidodicarbonate

To B8 (0.15 g, 0.29 mmol) in DCM (1.0 mL) was added 5-cyanopicolinicacid (0.051 g, 0.34 mmol) and T3P (50 wt % in EtOAc, 0.20 mL, 0.34mmol). The reaction was stirred at room temperature 3 h. The reactionwas added to saturated NaHCO₃ and stirred for several minutes. Themixture was then extracted with EtOAc. The combined organic layers werewashed with water and brine, dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified by preparative silica gel TLC (2×2000μm, 60% EtOAc/hexane) to provide B9.

Step 9:(R)-5-cyano-N-(4-fluoro-3-(9-imino-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)picolinamide

To B9 (0.16 g, 0.24 mmol) in DCM (1.2 mL) was added TFA (0.38 mL, 4.9mmol). The reaction was stirred at room temperature for 30 minutes. DCMwas added followed by saturated NaHCO₃. The mixture was extracted withDCM. The combined organic layers were washed with brine, dried (MgSO₄),filtered, and concentrated in vacuo to provide Example 1.

Using the appropriate carboxylic acid, the following Examples 2-12b wereprepared from B8 using the conditions described in Method B.

TABLE 1 LCMS BACE1 BACE2 m/z Ki Ki Ex. Structure IUPAC Name [M + H] (nM)(nM) 1

5-cyano-N-{4-fluoro- 3-[(7R)-9-imino-2,7- dimethyl-5,5-dioxido-5-thia-2,8- diazaspiro[3.5]non-7- yl]phenyl}pyridine-2-carboxamide 457.1 1.7 1.4 2

5-fluoro-N-{4-fluoro- 3-[(7R)-9-imino-2,7- dimethyl-5,5-dioxido-5-thia-2,8- diazaspiro[3.5]non-7- yl]phenyl}pyridine-2-carboxamide 450.1 6.1 1.2 3

N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}-5- methoxypyridine-2- carboxamide 462.26.3 1.6 4

N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}-5- methoxypyrazine-2- carboxamide 463.27.9 6.2 5

5-chloro-N-{4- fluoro-3-[(7R)-9- imino-2,7-dimethyl- 5,5-dioxido-5-thia-2,8-diazaspiro [3.5]non-7- yl]phenyl}pyridine-2- carboxamide 466.1 2.20.4 6

N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}-5- (trifluoromethoxy) pyridine-2-carboxamide 516.2 3.3 10.3  7

5-(difluoromethoxy)- N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5-dioxido-5-thia-2,8- diazaspiro[3.5]non-7- yl]phenyl}pyridine-2-carboxamide 498.1 2.7 4.3 8

N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}-5- (fluoromethoxy) pyridine-2-carboxamide 480.2 4.9 1.5 9

N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}-5- methoxy-3- methylpyridine-2-carboxamide 476.1 6.3 0.9 10 

N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}-5- methoxy-3- methylpyrazine-2-carboxamide 477.2 10.4  4.9 11 

5-cyano-N-{4-fluoro- 3-[(7R)-9-imino-2,7- dimethyl-5,5-dioxido-5-thia-2,8- diazaspiro[3.5]non-7- yl]phenyl}-3-methylpyridine-2- carboxamide 471.2 1.3 1.0 12 

5-(but-2-yn-1-yloxy)- N-{4-fluoro-3-[(7R)- 9-imino-2,7- dimethyl-5,5-dioxido-5-thia-2,8- diazaspiro[3.5]non-7- yl]phenyl}pyridine-2-carboxamide 500.3 2.3 30   12a

5-cyano-3- cyclopropyl-N-{4- fluoro-3-[(7R)-9- imino-2,7-dimethyl-5,5-dioxido-5-thia- 2,8-diazaspiro [3.5]non-7- yl]phenyl}pyridine-2-carboxamide 1.3 0.8 12b

5-cyano-3- (difluoromethyl)-N- {4-fluoro-3-[(7R)-9- imino-2,7-dimethyl-5,5-dioxido-5-thia- 2,8-diazaspiro [3.5]non-7- yl]phenyl}pyridine-2-carboxamide 507.1 1.4 0.5According to Method B and using the appropriate pyrrolidine-basedsulfone reagent in step 3 and the appropriate carboxylic acid in step 8,Examples 13-24 are prepared.

TABLE 2 Ex. Structure IUPAC NAME 13

5-cyano-N-(4-fluoro-3-((8R)- 10-imino-2,8-dimethyl-6,6-dioxido-6-thia-2,9- diazaspiro[4.5]decan-8- yl)phenyl)picolinamide 14

5-fluoro-N-(4-fluoro-3-((8R)- 10-imino-2,8-dimethyl-6,6-dioxido-6-thia-2,9- diazaspiro[4.5]decan-8- yl)phenyl)picolinamide 15

N-(4-fluoro-3-((8R)-10-imino- 2,8-dimethyl-6,6-dioxido-6-thia-2,9-diazaspiro[4.5]decan- 8-yl)phenyl)-5- methoxypicolinamide 16

N-(4-fluoro-3-((8R)-10-imino- 2,8-dimethyl-6,6-dioxido-6-thia-2,9-diazaspiro[4.5]decan- 8-yl)phenyl)-5- methoxypyrazine-2-carboxamide 17

5-chloro-N-(4-fluoro-3-((8R)- 10-imino-2,8-dimethyl-6,6-dioxido-6-thia-2,9- diazaspiro[4.5]decan-8- yl)phenyl)picolinamide 18

N-(4-fluoro-3-((8R)-10-imino- 2,8-dimethyl-6,6-dioxido-6-thia-2,9-diazaspiro[4.5]decan- 8-yl)phenyl)-5-(trifluoromethoxy)picolinamide 19

5-(difluoromethoxy)-N-(4- fluoro-3-((8R)-10-imino-2,8-dimethyl-6,6-dioxido-6-thia- 2,9-diazaspiro[4.5]decan-8-yl)phenyl)picolinamide 20

N-(4-fluoro-3-((8R)-10-imino- 2,8-dimethyl-6,6-dioxido-6-thia-2,9-diazaspiro[4.5]decan- 8-yl)phenyl)-5-(fluoromethoxy)picolinamide 21

N-(4-fluoro-3-((8R)-10-imino- 2,8-dimethyl-6,6-dioxido-6-thia-2,9-diazaspiro[4.5]decan- 8-yl)phenyl)-5-methoxy-3-methylpicolinamide 22

N-(4-fluoro-3-((8R)-10-imino- 2,8-dimrthyl-6,6-dioxido-6-thia-2,9-diazaspiro[4.5]decan- 8-yl)phenyl)-5-methoxy-3-methylpyrazine-2-carboxamide 23

5-cyano-N-(4-fluoro-3-((8R)- 10-imino-2,8-dimethyl-6,6-dioxido-6-thia-2,9- diazaspiro[4.5]decan-8- yl)phenyl)-3-methylpicolinamide 24

5-(but-2-yn-1-yloxy)-N-(4- fluoro-3-((8R)-10-imino-2,8-dimethyl-6,6-dioxido-6-thia- 2,9-diazaspiro[4.5]decan-8-yl)phenyl)picolinamide

Method C

Step 1: Using the conditions described in Method B step 3 except that B2is used instead of B3, A2 is converted to C1.Step 2: Using the conditions described in step 4 of Method B, C1 isconverted to C2.Step 3: To C2 in DCM at 0° C. is added triethylamine followed by oneequivalent of allyl chloroformate. The reaction is stirred for 8 hoursallowing the cold bath to expire. The mixture is diluted with DCM andwashed with saturated NaHCO₃, water, and brine. The organic layer isdried (MgSO₄), filtered, and concentrated in vacuo to provide C3.Step 4: Using the conditions described in step 5 of Method B, C3 isconverted to C4. C4 is purified by silica gel chromatography.Step 5: To C4 in DCM at room temperature is added 2.5 equivalents of(Boc)₂O and 0.1 equivalents of 4-dimethylaminopyridine. The reaction isstirred at room temperature for 12 hours and then diluted with DCM. Themixture is washed with water and brine. The organic layer is dried(MgSO₄), filtered, and concentrated in vacuo. The residue is purified bysilica gel chromatography using EtOAc and hexane to provide C5.Step 6: C5 is converted to C6 using the conditioins described in step 7of Method B.Step 7: C6 is converted to C7 using the conditions described in step 8of Method B except using 5-methoxypicolinic acid instead of5-cyanopicolinic acid.Step 8: To C7 in 1:1 acetonitrile/water is added diethylamine andtetrakis(triphenylphosphine)palladium. The reaction is stirred at roomtemperature for 20 h and then concentrated in vacuo. The residue ispartitioned between EtOAc and brine. The mixture is extracted withEtOAc. The combined organic layers are washed with brine, dried (MgSO₄),filtered, and concentrated in vacuo. The residue is purified by silicagel chromatography using EtOAc and hexanes as the eluent to provide C8.

Method Ca

Example 29

(R)-5-chloro-N-(4-fluoro-3-(5-imino-3,9-dimethyl-1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undecan-3-yl)phenyl)picolinamide(Method Ca) STEP 1:(R)-tert-butyl(3-(5-(5-chloropicolinamido)-2-fluorophenyl)-3,9-dimethyl-1,1-dioxido- 1-thia-4,9-diazaspiro[5.5]undecan-5-ylidene)carbamate

To a solution of 5-chloropicolinic acid (38 mg, 0.219 mmol) intetrahydrofuran (2 mL) at room temperature was addedN,N-diisopropylethylamine (0.058 mL, 0.33 mmol) and 50% solution of T3Pin ethyl acetate (0.2 mL, 0.308 mmol). The reaction mixture was stirredat room temperature for 15 min. Intermediate Ac12 (100 mg, 0.242 mmol)was dissolved in THF (3 mL) was then added slowly to the reaction andthe reaction mixture was further stirred at room temperature for 3 h.After the completion of the reaction, the reaction was quenched byadding water, extracted with ethyl acetate and the combined organiclayer was washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated to yield the crude product Cal which was carried on to thenext step without further purification.

STEP 2:(R)-5-chloro-N-(4-fluoro-3-(5-imino-3,9-dimethyl-1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undecan-3-yl)phenyl)picolinamide

To a solution of compound Cal (120 mg, 0.202 mmol) in dichloromethane (2mL), was added TFA (1 mL) at 0° C. and the reaction mixture was allowedto attain room temperature and stirred for 2 h. The reaction mixture wasconcentrated under reduced pressure. The crude thus obtained waspurified by Prep HPLC to yield title compound Example 29.

Method for Prep HPLC

Column: Sunfire Prep C18 OBD (19×250 mm) 5 micron; Column temp: Ambient;Mobile phase: A: 0.1% TFA in water, B: 100% Methanol; Gradient: From 0to 20 min 95:05 to 50:50 (A:B), from 21-25 mins 50:50 to 40:60 (A:B),from 25 to 26 mins 40:60 to 0:100 (A:B), from 26 to 30 mins 0:100 (A:B)to 0:100 (A:B), 30 to 31 mins 0:100 to 95:05 (A:B); 31 to 36 mins 95:05(A:B) to 95:05 (A:B); Flow rate: 10 mL/min; UV detection: 215 nm.

Method Cb

To a set of vials containing the requisite carboxylic acid (0.11 mmol)was added a solution of intermediate Bal2 (30 mg, 0.054 mmol) in DCM(1.0 mL) followed by the addition of a solution of T3P (50% in EtOAc,0.065 mL, 0.11 mmol) and DIEA (0.028 mL, 0.16 mmol). The vials werecapped and the mixtures were stirred at RT for 2.5 days. After thattime, water (0.1 mL) was added to each vial and the mixtures werestirred at RT for 5 min. To each vial was then added TFA (0.5 mL). Theresultant mixtures were stirred at RT for 4 hours followed byconcentration in vacuo. The crude residues were dissolved in DMSO (1 mL)and filtered. The crude products were purified by mass triggered HPLCusing the following conditions: [column: Waters XBridge C18, 5 μm,19×100 mm; solvent: gradient range 25-30% initial to 55-65% final MeCN(0.1% NH₄OH) in water (0.1% NH₄OH) 50 mL/min; 8 min run time] to affordExamples 25, 28, 30, 31, 32, 33, 34, 35, and 36.

TABLE 3 Using the appropriate carboxylic acid, Examples 26, 27, 36a, and36b were prepared using the procedure described in Method Ca. LCMS BACE1BACE2 m/z Ki Ki Ex. Structure IUPAC NAME [M + H] (nM) (nM) 25

5-cyano-N-{4-fluoro- 3-[(3R)-5-imino-3,9- dimethyl-1,1-dioxido-1-thia-4,9- diazaspiro[5.5]undec- 3-yl]phenyl}pyridine- 2-carboxamide485.2   6.4   8.4 26

5-fluoro-N-{4-fluoro- 3-[(3R)-5-imino-3,9- dimethyl-1,1-dioxido-1-thia-4,9- diazaspiro[5.5]undec- 3-yl]phenyl}pyridine- 2- carboxamide478.2 37   6.4 27

N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undec- 3-yl]phenyl}-5- methoxypyridine-2- carboxamide490.1 35 24 28

N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undec- 3-yl]phenyl}-5- methoxypyrazine-2- carboxamide491.2 19 29 29

5-chloro-N-{4-fluoro- 3-[(3R)-5-imino-3,9- dimethyl-1,1-dioxido-1-thia-4,9- diazaspiro[5.5]undec- 3-yl]phenyl}pyridine- 2- carboxamide494.0 12   3.0 30

N-!4-fluoro-3-[(3R)-5- imino-3,9-dimcthyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undec- 3- yl]phenyl}-5- (trifluoromethoxy)pyri-dine-2-carboxamide 544.2 15 52 31

5-(difluoromethoxy)- N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl-1,1-dioxido-1-thia-4,9- diazaspiro[5.5]undec- 3-yl]phenyl}pyridine-2-carboxamide 526.2 11 27 32

N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undec- 3-yl]phenyl}-5- (fluoromethoxy) pyridine-2-carboxamide 508.2 14 11 33

N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undec- 3-yl]phenyl}-5- methoxy-3- methylpyridine-2-carboxamide 504.2 37 23 34

N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undec- 3-yl]phenyl}-5- methoxy-3- methylpyrazine-2-carboxamide 505.2 37 23 35

5-cyano-N-{4-fluoro- 3-[(3R)-5-imino-3,9- dimethyl-1,1-dioxido-1-thia-4,9- diazaspiro[5.5]undec- 3-yl]phenyl}-3- methylpyridine-2-carboxamide 499.2 35 24 36

5-(but-2-yn-1-yloxy)- N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl-1,1-dioxido-1-thia-4,9- diazaspiro[5.5]undec- 3-yl]phenyl}pyridine-2-carboxamide 528.2   2.3 30  36a

2,2-difluoro-N-{4- fluoro-3-[(3R)-5- imino-3,9-dimethyl-1,1-dioxido-1-thia-4,9- diazaspiro[5.5]undec- 3-yl]phenyl}acetamide443.2 1710  210   36b

N-{4-fluoro-3-[(3R)-5- imino-3,9-dimethyl- 1,1-dioxido-1-thia-4,9-diazaspiro[5.5]undec- 3-yl]phenyl}-2- methoxyacetamide 427.2 548  56

Method Cc

Example 36c

(R)-5-cyano-N-(4-fluoro-3-(9-imino-7-methyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)picolinamide(Method Cc) Step 1: (R)-tert-butyl9-((tert-butoxycarbonyl)imino)-7-(5-(5-cyanopicolinamido)-2-fluorophenyl)-7-methyl-5-thia-2,8-diazaspiro[3.5]nonane-2-carboxylate5,5-dioxide

To Ad5 (0.07 g, 0.14 mmol) in DCM (0.5 mL) at room temperature was added5-cyanopicolinic acid (0.022 g, 0.15 mmol) followed by T3P (50% solutionin EtOAc, 0.098 mL, 0.16 mmol). The reaction was stirred for 18 h afterwhich saturated NaHCO₃ was added. The reaction was stirred for 5 minutesand then extracted with EtOAc. The combined organic layers were washedwith water and brine, dried (MgSO₄), filtered, and concentrated invacou. The residue was purified by silica gel chromatograpy (0-40%EOAc/hex over 30 minutes) to provide Cc1.

Step 2:(R)-5-cyano-N-(4-fluoro-3-(9-imino-7-methyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)picolinamide

To Cc1 (0.068 g, 0.11 mmol) in DCM (0.4 mL) at room temperature wasadded TFA (0.041 mL, 0.53 mmol). The reaction was stirred for 3 h andthen concentrated in vacuo. DCM was added and the reaction was washedwith saturated NaHCO3, water, and brine. The organic layer was dried(MgSO₄), filtered, and concentrated in vacuo. The residue was purifiedby SFC (AS column, 50% MeOH (0.2% DEA)/CO₂, 70 mL/min, 100 bar, 9 mg/mLin MeOH/DCM), 35C, 220 nM) to provide Example 36c.

Method Cd

Example 36d

(R)—N-(4-fluoro-3-(9-imino-7-methyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)-5-methoxypicolinamide(Method Cd) Step 1: (R)-tert-butyl7-(5-nitro-2-fluorophenyl)-9-((di-tert-butoxycarbonyl)amino)-7-methyl-5-thia-2,8-diazaspiro[3.5]non-8-ene-2-carboxylate5,5-dioxide

To a solution of Ad3 (0.7 g, 1.58 mmol) in dichloromethane (10 mL) atroom temperature was added (Boc)₂O (1.38 g, 6.33 mmol) followed by DMAP(0.02 g, 0.15 mmol). The mixture was stirred for 4 h at roomtemperature. The reaction was loaded directly onto a silica gel columnand purified eluting with 0- 20% EtOAc/Petroleum ether to provide Cd1.

Step 2: (R)-tert-butyl7-(5-amino-2-fluorophenyl)-9-((di-tert-butoxycarbonyl)amino)-7-methyl-5-thia-2,8-diazaspiro[3.5]non-8-ene-2-carboxylate5,5-dioxide

To a solution of Cd1 (0.5 g, 0.78 mmol) in THF (6 mL) at roomtemperature was added PMHS (0.29 mL, 0.85 mmol), potassium fluoride(0.13 g, 1.5 mmol) in water (1.4 mL) and palladium (II) acetate (0.013g, catalytic) [gas evolution]. The reaction mixture was stirred at roomtemperature for 2 h. To the reaction mixture was added water andextracted with EtOAc. The EtOAc layer was washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-40% EtOAc/petroleum ether) toprovide Cd2.

Step 3: (R)-tert-butyl9-((di-tert-butoxycarbonyl)amino)-7-(2-fluoro-5-(5-methoxypicolinamido)phenyl)-7-methyl-5-thia-2,8-diazaspiro[3.5]non-8-ene-2-carboxylate5,5-dioxide

To a solution of Cd2 (0.38 g, 0.62 mmol) in dichloromethane (10 mL) atroom temperature was added 5-methoxy picolinic acid (0.14 g, 0.93 mmol)followed by T3P (50% solution in EtOAc, 1.0 mL, 1.8 mmol) and DIEA (0.54mL, 3.1 mmol). The reaction was stirred for 16 h after which saturatedNaHCO₃ was added. The reaction mixture was extracted withdichloromethane. The combined organic layers were washed with water andbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by silica gel chromatography (0-30%EOAc/petroleum ether) to provide Cd3.

Step 4:(R)—N-(4-fluoro-3-(9-imino-7-methyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)-5-methoxypicolinamide

To a solution of A8 (0.3 g) in dichloromethane (5 mL) at roomtemperature was added TFA (10 mL). The reaction was stirred for 4 h andthen concentrated in vacuo. The residue was triturated with ether andthen dried under vacuum to provide Example 36d as a TFA salt.

Example 36e

5-cyano-N-{4-fluoro-3-[(7R)-9-imino-7-methyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]non-7-yl]phenyl}-3-methylpyridine-2-carboxamide

Using the conditions described in Method Cc, Intermediate Ad5 wasconverted to Example 36e using 5-cyano-3-methylpicolinic acid in step 1instead of 5-cyanopicolinic acid.

TABLE 3a LCMS BACE1 BACE2 m/z Ki Ki Ex. Structure IUPAC Name [M + H](nM) (nM) 36c

5-cyano-N-{4-fluoro-3- [(7R)-9-imino-7-methyl- 5,5-dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}pyridine-2- carboxamide 443.0 3.7 2.636d

(R)-N-(4-fluoro-3-(9- imino-7-methyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7- yl)phenyl)-5- methoxypicolinamide 448.2 22  16   36e

5-cyano-N-{4-fluoro-3- [(7R)-9-imino-7-methyl- 5,5-dioxido-5-thia-2,8-diazaspiro[3.5]non-7- yl]phenyl}-3- methylpyridinc-2- carboxamide 457.24.1 1.8

Step 1: To C8 in THF at room temperature is added acetic acid followedby T3P. The reaction is stirred at room temperature for 8 hours. Wateris added and the reaction is stirred for 5 minutes. The mixture isextracted with EtOAc. The combined organic layers are washed withsaturated NaHCO₃, water, and brine. The organic layer is dried (MgSO₄),filtered, and concentrated in vacuo. The residue is purified by silicagel chromatography to provide D1.Step 2: To D1 in DCM at room temperature is added 5 equivalents of TFA.The reaction is stirred at room temperature for 2 hours and thenconcentrated in vacuo. The residue is taken up into DCM and stirred withsaturated NaHCO₃. The mixture is extracted with DCM. The combinedorganic layers are washed with water and brine, dried (MgSO₄), filtered,and concentrated in vacuo to provide Example 37.

Method Da

Example 37

(R)—N-(3-(2-acetyl-9-imino-7-methyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)-4-fluorophenyl)-5-methoxypicolinamide(Method Da)

To a solution of Example 36d (0.05 g, 0.118 mmol) in dichloromethane (5mL) at 0° C. was added triethylamine (catalytic amount) followed byacetyl chloride (0.008 g, 0.118 mmol) [Note: Acetyl chloride was addedas stock solution in dichloromethane (100 mg/20 mL)=1.6 mL]. Thereaction mixture was allowed to warm to RT and stirred for 2 h. Thereaction was purified directly by silica gel chromatography (0-5%MeOH/dichloromethane) to provide Example 37.

Method E

Step 1: To C8 in DCM at room temperature is added TEA followed bymethanesulfonyl chloride. The reaction is stirred at room temperaturefor 2 h. The mixture is then diluted with DCM and washed with saturatedNaHCO₃, water, and brine. The organic layer is dried (MgSO₄), filtered,and concentrated in vacuo. The residue is purified by silica gelchromatography to provide E1.Step 2: To E1 in DCM at room temperature is added 5 equivalents of TFA.The reaction is stirred at room temperature for 2 hours and thenconcentrated in vacuo. The residue is taken up into DCM and stirred withsaturated NaHCO₃. The mixture is extracted with DCM. The combinedorganic layers are washed with water and brine, dried (MgSO₄), filtered,and concentrated in vacuo to provide Example 38.

Method Ea

Example 38

(R)—N-(4-fluoro-3-(9-imino-7-methyl-2-(methylsulfonyl)-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)-5-methoxypicolinamide(Method Ea)

To a solution of Example 36d (0.05 g, 0.118 mmol) in dichloromethane (5mL) at 0° C. was added triethylamine (catalytic amount) followed bymethane sulfonyl chloride (0.012 g, 0.118 mmol) [Note: by methanesulfonyl chloride was added as stock solution in dichloromethane (100 mgin 20 mL)=2.4 mL]. The reaction mixture was allowed to warm to RT andstirred for 2 h. The reaction was purified directly by silica gelchromatography (0-5% MeOH/dichloromethane) to provide Example 38.

Method F

Step 1: To C8 in DCM at room temperature is added TEA followed bymethylisocyanate. The reaction is stirred at room temperature for 3 h.The reaction is diluted with DCM and washed with water and brine. Theorganic layer is dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue is purified by silica gel chromatography to provide F1.Step 2: To F1 in DCM at room temperature is added 5 equivalents of TFA.The reaction is stirred at room temperature for 2 hours and thenconcentrated in vacuo. The residue is taken up into DCM and stirred withsaturated NaHCO₃. The mixture is extracted with DCM. The combinedorganic layers are washed with water and brine, dried (MgSO₄), filtered,and concentrated in vacuo to provide Example 39.

Method Fa

Example 39

(R)-7-(2-fluoro-5-(5-methoxypicolinamido)phenyl)-9-imino-N,7-dimethyl-5-thia-2,8-diazaspiro[3.5]nonane-2-carboxamide5,5-dioxide (Method Fa)

To a solution of Example 36d (0.05 g, 0.118 mmol) in dichloromethane (5mL) at 0° C. was added triethylamine (catalytic amount) followed byN-methyl amino formyl chloride (0.012 g, 0.118 mmol) [Note: N-methylamino formyl chloride was added as stock solution in dichloromethane(100 mg in 20 ml)=2.1 mL]. The reaction mixture was allowed to warm toRT and stirred for 2 h. The reaction was purified directly by silica gelchromatography (0-5% MeOH/dichloromethane) to provide Example 39.

Method G

Step 1: To C8 in dichloroethane at room temperature is addedbenzaldehyde followed by sodium triacetoxyborohydride. The reaction isstirred at room temperature for 12 hours and then diluted with DCM. Themixture is washed with saturated NaHCO₃, water, and brine. The organiclayer is dried (MgSO₄), filtered, and concentrated in vacuo. The residueis purified by silica gel chromatography to provide G1.Step 2: To G1 in DCM at room temperature is added 5 equivalents of TFA.The reaction is stirred at room temperature for 2 hours and thenconcentrated in vacuo. The residue is taken up into DCM and stirred withsaturated NaHCO₃. The mixture is extracted with DCM. The combinedorganic layers are washed with water and brine, dried (MgSO₄), filtered,and concentrated in vacuo to provide Example 40.

Method Ga

Example 40

(R)—N-(3-(2-benzyl-9-imino-7-methyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)-4-fluorophenyl)-5-methoxypicolinamide(Method Ga)

To a solution of Example 36d (0.05 g, 0.118 mmol) in THF (5 mL) at 0° C.was added acetic acid (1 drop) followed by benzaldehyde (0.011 g, 0.118mmol) The reaction was stirred for 16 h at room temperature after whichMeOH (2 mL) followed by NaCNBH₃ (0.014 g, 0.237 mmol) were added. Thereaction was then stirred for 4 h. The reaction was purified directly bysilica gel chromatography (0-5% MeOH/dichloromethane over 30 minutes) toprovide Example 40.

Method H

Step 1: To C8 in THF at room temperature is added a base such aspotassium carbonate or potassium tert-butoxide followed by a palladiumcatalyst such as X-Phos(2-Dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl) or RuPhos(Chloro-(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct).Bromobenzene is added and the reaction is warmed to between 50 and 80°C. for 12 h. The cooled reaction is diluted with EtOAc and filteredthrough a plug of Celite. The filtrate is washed with water and brine,dried (MgSO₄), filtered, and concentrated in vacuo. The residue ispurified by silica gel chromatography to provide H1.Step 2: To H1 in DCM at room temperature is added 5 equivalents of TFA.The reaction is stirred at room temperature for 2 hours and thenconcentrated in vacuo. The residue is taken up into DCM and stirred withsaturated NaHCO₃. The mixture is extracted with DCM. The combinedorganic layers are washed with water and brine, dried (MgSO₄), filtered,and concentrated in vacuo to provide Example 41.

Method I

Example 42

(R)—N-(4-fluoro-3-(9-imino-7-methyl-2-(4-nitrophenyl)-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)-5-methoxypicolinamide(Method I)

To a solution of Example 36d (0.03 g, 0.067 mmol) inN-Methyl-2-pyrrolidone (1 mL) at room temperature was added potassiumtert-butoxide (0.022 g, 0.201 mmol) followed by 1-fluoro-4-nitrobenzene(0.028 g, 0.201 mmol). The reaction mixture was heated at 60° C. for 2h. Fluoro 4-nitrobenzene (0.028 g, 0.201 mmol) and potassiumtert-butoxide (0.022 g, 0.201 mmol) were added again and the reactionstirred at 60° C. for an additional 1 h. The reaction mixture was cooledto room temperature and the volatiles removed under reduced pressure.The crude thus obtained was purified by silica gel chromatography using5% methanol in dichloromethane to provide Example 42.

TABLE 4 LCMS BACE1 BACE2 m/z Ki Ki Ex. Structure IUPAC Name [M+H] (nM)(nM) 37

(R)-N-(3-(2-acetyl-9- imino-7-methyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7- yl)-4-fluorophenyl)-5- methoxypicolinamide 490.21.6 1.1 38

(R)-N-(4-fluoro-3-(9- imino-7-methyl-2- (methylsulfonyl)-5,5-dioxido-5-thia-2,8- diazaspiro[3.5]nonan-7- yl)phenyl)-5-methoxypicolinamide 526.0 6.5 2.3 39

(R)-7-(2-fluoro-5-(5- methoxypicolinamido) phenyl)-9-imino-N,7-dimethyl-5-thia-2,8- diazaspiro[3.5]nonane-2- carboxamide 5,5-dioxide505.4 7.3 1.7 40

(R)-N-(3-(2-benzyl-9- imino-7-methyl-5,5- dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7- yl)-4-fluorophenyl)-5- methoxypicolinamide 538.27.7 0.6 41

(R)-N-(4-fluoro-3-(9- imino-7-methyl-5,5- dioxido-2-phenyl-5-thia-2,8-diazaspiro[3.5]nonan- 7-yl)phenyl)-5- methoxypicolinamide 42

(R)-N-(4-fluoro-3-(9- imino-7-methyl-2-(4- nitrophenyl)-5,5-dioxido-5-thia-2,8- diazaspiro[3.5]nonan-7- yl)phenyl)-5- methoxypicolinamide569.4 1.4 0.32

LCMS Conditions

Method A: Conditions D: System: Waters Acquity UPLC/MS, Electrospraypositive ion mode; Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7micron; Mobile Phase: A: H2O/0.05% TFA, B: ACN/0.05% TFA; Gradient:0-1.8 min, 5-99% B; Flow Rate: 0.8 mL/min; UV: 254 nm

Assays

Protocols that used to determine the recited potency values for thecompounds of the invention are described below.

BACE1 HTRF FRET Assay Reagents: Na⁺-Acetate pH 5.0; 1% Brij-35;Glycerol; Dimethyl Sulfoxide (DMSO);

Recombinant human soluble BACE1 catalytic domain (>95% pure); APPSwedish mutant peptide substrate (QSY7-APP^(swe)-Eu):QSY7-EISEVNLDAEFC-Europium-amide.

A homogeneous time-resolved FRET assay can be used to determine IC₅₀values for inhibitors of the soluble human BACE1 catalytic domain. Thisassay monitors the increase of 620 nm fluorescence that resulted fromBACE1 cleavage of an APPswedish APP^(swe) mutant peptide FRET substrate(QSY7-EISEVNLDAEFC-Europium-amide). This substrate contains anN-terminal QSY7 moiety that serves as a quencher of the C-terminalEuropium fluorophore (620 nm Em). In the absence of enzyme activity, 620nm fluorescence is low in the assay and increased linearly over 3 hoursin the presence of uninhibited BACE1 enzyme. Inhibition of BACE1cleavage of the QSY7-APP^(swe)-Eu substrate by inhibitors is manifestedas a suppression of 620 nm fluorescence.

Varying concentrations of inhibitors at 3× the final desiredconcentration in a volume of 10 ul are preincubated with purified humanBACE1 catalytic domain (3 nM in 10 μl) for 30 minutes at 30° C. inreaction buffer containing 20 mM Na-Acetate pH 5.0, 10% glycerol, 0.1%Brij-35 and 7.5% DSMO. Reactions are initiated by addition of 10 μl of600 nM QSY7-APP^(swe)-Eu substrate (200 nM final) to give a finalreaction volume of 30 μl in a 384 well Nunc HTRF plate. The reactionsare incubated at 30° C. for 1.5 hours. The 620 nm fluorescence is thenread on a Rubystar HTRF plate reader (BMG Labtechnologies) using a 50millisecond delay followed by a 400 millisecond acquisition time window.Inhibitor IC₅₀ values are derived from non-linear regression analysis ofconcentration response curves. K_(i) values are then calculated fromIC₅₀ values using the Cheng-Prusoff equation using a previouslydetermined μm value of 8 μM for the QSY7-APP^(swe)-Eu substrate atBACE1.

BACE-2 Assay

Inhibitor IC_(50s) at purified human autoBACE-2 are determined in atime-resolved endpoint proteolysis assay that measures hydrolysis of theQSY7-EISEVNLDAEFC-Eu-amide FRET peptide substrate (BACE-HTRF assay).BACE-mediated hydrolysis of this peptide results in an increase inrelative fluorescence (RFU) at 620 nm after excitation with 320 nmlight. Inhibitor compounds, prepared at 3× the desired finalconcentration in 1×BACE assay buffer (20 mM sodium acetate pH 5.0, 10%glycerol, 0.1% Brij-35) supplemented with 7.5% DMSO are pre-incubatedwith an equal volume of autoBACE-2 enzyme diluted in 1×BACE assay buffer(final enzyme concentration 1 nM) in black 384-well NUNC plates for 30minutes at 30° C. The assay is initiated by addition of an equal volumeof the QSY7-EISEVNLDAEFC-Eu-amide substrate (200 nM final concentration,K_(m)=8 μM for 4 μM for autoBACE-2) prepared in 1×BACE assay buffersupplemented with 7.5% DMSO and incubated for 90 minutes at 30° C. DMSOis present at 5% final concentration in the assay. Following laserexcitation of sample wells at 320 nm, the fluorescence signal at 620 nmis collected for 400 ms following a 50 μs delay on a RUBYstar HTRF platereader (BMG Labtechnologies). Raw RFU data is normalized to maximum (1.0nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values. IC_(50s) aredetermined by nonlinear regression analysis (sigmoidal dose response,variable slope) of percent inhibition data with minimum and maximumvalues set to 0 and 100 percent respectively. Similar IC_(50s) areobtained when using raw RFU data. The K_(i) values are calculated fromthe IC₅₀ using the Cheng-Prusoff equation.

We claim:
 1. A compound, or a pharmaceutically acceptable salt thereof,said compound having the structural Formula (I):

or a tautomer thereof having the structural Formula (I′):

or pharmaceutically acceptable salt thereof, wherein: R^(1A) is selectedfrom the group consisting of H, halo, alkyl, cycloalkyl, haloalkyl, andheteroalkyl; R^(1B) is selected from the group consisting of H, halo,alkyl, cycloalkyl, haloalkyl, and heteroalkyl; ring C is a moietyselected from the group consisting of

each R² is independently selected from the group consisting of H,-alkyl-OH, alkyl, heteroalkyl, and cycloalkyl wherein each said alkyl,heteroalkyl, and cycloalkyl of R² is optionally substituted withhalogen; each R³ is independently selected from the group consisting ofH, halogen, -alkyl-OH, alkyl, heteroalkyl, alkoxy, and cycloalkyl,wherein each said alkyl, heteroalkyl, alkoxy, and cycloalkyl of R³ isoptionally substituted with halogen; R^(N) is selected from the groupconsisting of: H, —C(O)R^(6N), —C(O)OR^(6N), —C(O)N(R^(6N))₂,—S(O)₂R^(6N), —S(O)₂N(R^(6N))₂, alkyl, heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein said alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl, of R^(N) are each optionally independentlyunsubstituted or substituted with one or more groups independentlyselected from R⁹; R⁴ is selected from the group consisting of H, alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl is optionally substituted with one or morehalogen; ring A is selected from the group consisting of aryl,monocyclic heteroaryl, and a multicyclic group; m is 0 or more; eachR^(A) (when present) is independently selected from the group consistingof: halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5A))₃, —N(R^(6A))₂,—OR^(6A), —SR^(6A), alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl ofR^(A) are each optionally independently unsubstituted or substitutedwith one or more groups independently selected from R⁸; -L₁- is adivalent moiety selected from the group consisting of —NHC(O)— and—C(O)NH—; R^(L) is selected from the group consisting of alkyl andheteroalkyl, wherein said alkyl and heteroalkyl of R^(L) are eachoptionally unsubstituted or substituted with one or more halogen; or,alternatively, R^(L) is a moiety having the formula

wherein q is 0 or 1; -L_(B)- (when present) is a divalent moietyselected from the group consisting of lower alkyl and lower heteroalkyl,wherein each said lower alkyl and lower heteroalkyl is optionallysubstituted with one or more halogen; ring B is selected from the groupconsisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl,monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclicheterocycloalkenyl, and a multicyclic group; p is 0 or more; and eachR^(B) (when present) is independently selected from the group consistingof: halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5B))₃, —N(R^(6B))₂,—NR^(7B)C(O)R^(6B), —NR⁷BS(O)₂R^(6B), —NR^(7B)S(O)₂N(R^(6B))₂,—NR^(7B)C(O)N(R^(6B))₂, —NR^(7B)C(O)OR^(6B), —C(O)R^(6B), —C(O)OR^(6B),—C(O)N(R^(6B))₂, —S(O)R^(6B), S(O)₂R^(6B), —S(O)₂N(R^(6B))₂, —OR^(6B),—SR^(6B), alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl. wherein said alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,heteroaryl, and -alkyl-heteroaryl, of R^(B) are each optionallyindependently unsubstituted or substituted with one or more groupsindependently selected from R⁹; each R^(5A) and R^(5B) (when present) isindependently selected from the group consisting of alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkylof R^(5A) and R^(5B) is unsubstituted or substituted with one or morehalogen; each R^(6N) and R^(6A) (when present) is independently selectedfrom the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl,heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl,-alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R^(6N) and R^(6A) isunsubstituted or substituted with one or more groups independentlyselected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl,alkoxy, heteroalkoxy, and haloalkoxy; each R^(6B) (when present) isindependently selected from the group consisting of H, alkyl, -alkyl-OH,alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein each said alkyl,-alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R^(6B) isunsubstituted or substituted with one or more groups independentlyselected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl,alkoxy, heteroalkoxy, and haloalkoxy; each R^(7B) (when present) isindependently selected from the group consisting of H, alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl of R^(7B) is unsubstituted or substituted withone or more halogen; each R⁸ (when present) is independently selectedfrom the group consisting of halogen, lower alkyl, lower heteroalkyl,lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl, wherein eachsaid lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, andlower heterocycloalkyl of R⁸ is optionally substituted with halogen; andeach R⁹ (when present) is independently selected from the groupconsisting of halogen, —NO₂, —OH, —CN, —SF₅, —OSF₅, alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl are optionally substituted with one or morehalogen.
 2. A compound of claim 1, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or said tautomer,wherein: each R² is H; each R³ (when present) is H; R^(1A) is H; R^(1B)is H; R⁴ is selected from the group consisting of methyl and —CHF₂; andR^(N) is selected from the group consisting of H, —C(O)CH₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)O-cyclopropyl,—C(O)O—CH₂-cyclopropyl, —C(O)N(CH₃)₂, —C(O)NHCH₃, C(O)-aryl,C(O)-heteroaryl, —S(O)₂CH₃, —S(O)₂-cyclopropyl, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —S(O)₂-aryl, —S(O)₂-heteroaryl, methyl, ethyl, propyl,isopropyl, cyclopropyl, —CH₂-cyclopropyl, benzyl, phenyl, pyridyl,pyrimidinyl, pyrazinyl, oxadiazoyl, isoxazoyl, oxazoyl, pyrrolyl,thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, —CH₂-heteroaryl,wherein said benzyl, phenyl, pyridyl, oxadiazoyl, isoxazoyl, oxazoyl,pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl,—CH₂-heteroaryl, C(O)-aryl, C(O)-heteroaryl, —S(O)₂-aryl,—S(O)₂-heteroaryl of R^(N) are each optionally unsubstituted orsubstituted with R⁹.
 3. A compound of claim 2, or a tautomer thereof, ora pharmaceutically acceptable salt of said compound or said tautomer,wherein: R^(N) is selected from the group consisting of H, —C(O)CH₃,—S(O)₂CH₃, —C(O)NHCH₃, methyl, benzyl, benzyl substituted with —NO₂,phenyl, and phenyl substituted with —NO₂.
 4. A compound of claim 3, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor said tautomer, wherein: ring A is selected from the group consistingof phenyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, andtetrazinyl; m is 0, 1, or 2; and each R^(A) (when present) isindependently selected from the group consisting of halogen, oxo, —CN,—SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl, cyclopropyl,—CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.
 5. A compoundof claim 4, or a tautomer thereof, or a pharmaceutically acceptable saltof said compound or said tautomer, wherein: R^(L) is selected from thegroup consisting of methyl, ethyl, propyl, butyl, —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃, —CH₂SCH₃,—CH₂SCH₂CH₃, —CH₂CH₂SCH₃, —CH₂N(CH₃)₂, —CH₂NHCH₃, —CH₂CH₂N(CH₃)₂,—CH₂OCF₃, and —CH₂OCHF₂.
 6. A compound of claim 4, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound or saidtautomer, wherein: R^(L) is a moiety having the formula

q is 0 or 1; -L_(B)- (when present) is a divalent moiety selected fromthe group consisting of —CH₂—, —CF₂—, —CH₂CH₂—, —CH₂O—, and —CF₂O—; ringB is selected from the group consisting of azetidinyl, benzimidazolyl,benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl, benzoxazoyl,cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dihydroindenyl,dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl; p is 0 or more; and each R^(B)group (when present) is independently selected from the group consistingof halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂, —NHC(O)CH₃,—N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂C H₃, —C(O)OCH₃, —C(O)OCH₂CH₃,—C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃,—OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C—C—H,—OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl, oxadiazoyl,isoxazoyl, oxazoyl, and pyrrolyl, wherein each said phenyl, pyridyl,oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl is optionally substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of F, Cl, CN, —CH₃, —OCH₃, and —CF₃.
 7. A compound of claim4, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer, wherein: R^(L) is a moiety having the formula

q is 0 or 1; -L_(B)- (when present) is a divalent moiety selected fromthe group consisting of —CH₂—, —CF₂—, —CH₂CH₂—, —CH₂O—, and —CF₂O—; ringB is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl; p is0 or more; and each R^(B) group (when present) is independently selectedfrom the group consisting of fluoro, chloro, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.
 8. A compound of claim 7, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor said tautomer, wherein: ring A is phenyl, m is 1 or 2, R^(A) isfluoro; -L₁- is —C(O)NH—; ring B is selected from the group consistingof phenyl, pyridyl, and pyrazinyl, p is 0, 1, or 2, and each R^(B) (whenpresent) is independently selected from the group consisting of fluoro,chloro, bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂, —NHC(O)CH₃,—N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃, —C(O)OCH₃, —C(O)OCH₂CH₃,—C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃,—OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H,—OCH₂—C≡C—CH₃—S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.
 9. A compound of claim1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer, said compound selected from the groupconsisting of: Ex. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

 12a

 12b

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

 36a

 36b

 36c

 36d

 36e

37

38

39

40

41

and 42


10. A pharmaceutical composition comprising at least one compoundaccording to claim 1, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or said tautomer, and apharmaceutically acceptable carrier or diluent.
 11. A method of treatingan indication selected from the group consisting of Alzheimer's disease,Down's syndrome, Parkinson's disease, stroke, microgliosis, braininflammation, pre-senile dementia, senile dementia, progressivesupranuclear palsy, cortical basal degeneration, olfactory impairmentassociated with Alzheimer's disease, olfactory impairment associatedwith Parkinson's disease, olfactory impairment associated with Down'ssyndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditarycerebral hemorrhage, mild cognitive impairment, glaucoma, amyloidosis,type II diabetes, diabetes-associated amyloidogenesis, scrapie, bovinespongiform encephalitis, traumatic brain injury, and Creutzfeld-Jakobdisease, said method comprising administering a compound according toclaim 1, or a tautomer thereof, or a or a pharmaceutically acceptablesalt of said compound or said tautomer, to a patient in need thereof.12. A method of claim 13, wherein said Aβ pathology is Alzheimer'sdisease.